Bertoli Avella, A.M.

Phenotypic spectrum of the SMAD3-related aneurysms-osteoarthritis syndrome (Article)

2012-01-01T00:00:00Z

Background: Aneurysmseosteoarthritis syndrome (AOS) is a new autosomal dominant syndromic form of thoracic aortic aneurysms and dissections characterised by the presence of arterial aneurysms and tortuosity, mild craniofacial, skeletal and cutaneous anomalies, and early-onset osteoarthritis. AOS is caused by mutations in the SMAD3 gene. Methods: A cohort of 393 patients with aneurysms without mutation in FBN1, TGFBR1 and TGFBR2 was screened for mutations in SMAD3. The patients originated from The Netherlands, Belgium, Switzerland and USA. The clinical phenotype in a total of 45 patients from eight different AOS families with eight different SMAD3 mutations is described. In all patients with a SMAD3 mutation, clinical records were reviewed and extensive genetic, cardiovascular and orthopaedic examinations were performed. Results Five novel SMAD3 mutations (one nonsense, two missense and two frame-shift mutations) were identified in five new AOS families. A follow-up description of the three families with a SMAD3 mutation previously described by the authors was included. In the majority of patients, early-onset joint abnormalities, including osteoarthritis and osteochondritis dissecans, were the initial symptom for which medical advice was sought. Cardiovascular abnormalities were present in almost 90% of patients, and involved mainly aortic aneurysms and dissections. Aneurysms and tortuosity were found in the aorta and other arteries throughout the body, including intracranial arteries. Of the patients who first presented with joint abnormalities, 20% died suddenly from aortic dissection. The presence of mild craniofacial abnormalities including hypertelorism and abnormal uvula may aid the recognition of this syndrome. Conclusion: The authors provide further insight into the phenotype of AOS with SMAD3 mutations, and present recommendations for a clinical work-up.

Congenital dyserythropoietic anemia type II: Molecular analysis and expression of the SEC23B Gene (Article)

2011-12-01T00:00:00Z

Background: Congenital dyserythropoietic anemia type II (CDAII), the most common form of CDA, is an autosomal recessive condition. CDAII diagnosis is based on invasive, expensive, and time consuming tests that are available only in specialized laboratories. The recent identification of SEC23B mutations as the cause of CDAII opens new possibilities for the molecular diagnosis of the disease. The aim of this study was to characterize molecular genomic SEC23B defects in 16 unrelated patients affected by CDAII and correlate the identified genetic alterations with SEC23B transcript and protein levels in erythroid precursors. Methods. SEC23B was sequenced in 16 patients, their relatives and 100 control participants. SEC23B transcript level were studied by quantitative PCR (qPCR) in peripheral erythroid precursors and lymphocytes from the patients and healthy control participants. Sec23B protein content was analyzed by immunoblotting in samples of erythroblast cells from CDAII patients and healthy controls. Results: All of the investigated cases carried SEC23B mutations on both alleles, with the exception of two patients in which a single heterozygous mutation was found. We identified 15 different SEC23B mutations, of which four represent novel mutations: p.Gln214Stop, p.Thr485Ala, p.Val637Gly, and p.Ser727Phe. The CDAII patients exhibited a 40-60% decrease of SEC23B mRNA levels in erythroid precursors when compared with the corresponding cell type from healthy participants. The largest decrease was observed in compound heterozygote patients with missense/nonsense mutations. In three patients, Sec23B protein levels were evaluated in erythroid precursors and found to be strictly correlated with the reduction observed at the transcript level. We also demonstrate that Sec23B mRNA expression levels in lymphocytes and erythroblasts are similar. Conclusions: In this study, we identified four novel SEC23B mutations associated with CDAII disease. We also demonstrate that the genetic alteration results in a significant decrease of SEC23B transcript in erythroid precursors. Similar down-regulation was observed in peripheral lymphocytes, suggesting that the use of these cells might be sufficient in the identification of Sec23B gene alterations. Finally, we demonstrate that decreased Sec23B protein levels in erythroid precursors correlate with down-regulation of the SEC23B mRNA transcript.

Identification of RNA binding motif proteins essential for cardiovascular development (Article)

2011-10-20T00:00:00Z

Background: We recently identified Rbm24 as a novel gene expressed during mouse cardiac development. Due to its tightly restricted and persistent expression from formation of the cardiac crescent onwards and later in forming vasculature we posited it to be a key player in cardiogenesis with additional roles in vasculogenesis and angiogenesis. Results: To determine the role of this gene in cardiac development, we have identified its zebrafish orthologs (rbm24a and rbm24b), and functionally evaluated them during zebrafish embryogenesis. Consistent with our underlying hypothesis, reduction in expression of either ortholog through injection of morpholino antisense oligonucleotides results in cardiogenic defects including cardiac looping and reduced circulation, leading to increasing pericardial edema over time. Additionally, morphant embryos for either ortholog display incompletely overlapping defects in the forming vasculature of the dorsal aorta (DA), posterior caudal vein (PCV) and caudal vein (CV) which are the first blood vessels to form in the embryo. Vasculogenesis and early angiogenesis in the trunk were similarly compromised in rbm24 morphant embryos at 48 hours post fertilization (hpf). Subsequent vascular maintenance was impaired in both rbm24 morphants with substantial vessel degradation noted at 72 hpf. Conclusion: Taken collectively, our functional data support the hypothesis that rbm24a and rbm24b are key developmental cardiac genes with unequal roles in cardiovascular formation.

Exome sequencing identifies SMAD3 mutations as a cause of familial thoracic aortic aneurysm and dissection with intracranial and other arterial aneurysms (Article)

2011-09-02T00:00:00Z

RATIONALE: Thoracic aortic aneurysms leading to acute aortic dissections (TAAD) can be inherited in families in an autosomal dominant manner. As part of the spectrum of clinical heterogeneity of familial TAAD, we recently described families with multiple members that had TAAD and intracranial aneurysms or TAAD and intracranial and abdominal aortic aneurysms inherited in an autosomal dominant manner. OBJECTIVE: To identify the causative mutation in a large family with autosomal dominant inheritance of TAAD with intracranial and abdominal aortic aneurysms by performing exome sequencing of 2 distantly related individuals with TAAD and identifying shared rare variants. METHODS AND RESULTS: A novel frame shift mutation, p. N218fs (c.652delA), was identified in the SMAD3 gene and segregated with the vascular diseases in this family with a logarithm of odds score of 2.52. Sequencing of 181 probands with familial TAAD identified 3 additional SMAD3 mutations in 4 families, p.R279K (c.836G>A), p.E239K (c.715G>A), and p.A112V (c.235C>T), resulting in a combined logarithm of odds score of 5.21. These 4 mutations were notably absent in 2300 control exomes. SMAD3 mutations were recently described in patients with aneurysms osteoarthritis syndrome and some of the features of this syndrome were identified in individuals in our cohort, but these features were notably absent in many SMAD3 mutation carriers. CONCLUSIONS: SMAD3 mutations are responsible for 2% of familial TAAD. Mutations are found in families with TAAD alone, along with families with TAAD, intracranial aneurysms, abdominal aortic and bilateral iliac aneurysms segregating in an autosomal dominant manner.

Microcephaly with simplified gyration, epilepsy, and infantile diabetes linked to inappropriate apoptosis of neural progenitors (Article)

2011-08-12T00:00:00Z

We describe a syndrome of primary microcephaly with simplified gyral pattern in combination with severe infantile epileptic encephalopathy and early-onset permanent diabetes in two unrelated consanguineous families with at least three affected children. Linkage analysis revealed a region on chromosome 18 with a significant LOD score of 4.3. In this area, two homozygous nonconserved missense mutations in immediate early response 3 interacting protein 1 (IER3IP1) were found in patients from both families. IER3IP1 is highly expressed in the fetal brain cortex and fetal pancreas and is thought to be involved in endoplasmic reticulum stress response. We reported one of these families previously in a paper on Wolcott-Rallison syndrome (WRS). WRS is characterized by increased apoptotic cell death as part of an uncontrolled unfolded protein response. Increased apoptosis has been shown to be a cause of microcephaly in animal models. An autopsy specimen from one patient showed increased apoptosis in the cerebral cortex and pancreas beta cells, implicating premature cell death as the pathogenetic mechanism. Both patient fibroblasts and control fibroblasts treated with siRNA specific for IER3IP1 showed an increased susceptibility to apoptotic cell death under stress conditions in comparison to controls. This directly implicates IER3IP1 in the regulation of cell survival. Identification of IER3IP1 mutations sheds light on the mechanisms of brain development and on the pathogenesis of infantile epilepsy and early-onset permanent diabetes.

Mutations in SMAD3 cause a syndromic form of aortic aneurysms and dissections with early-onset osteoarthritis (Article)

2011-02-01T00:00:00Z

Thoracic aortic aneurysms and dissections are a main feature of connective tissue disorders, such as Marfan syndrome and Loeys-Dietz syndrome. We delineated a new syndrome presenting with aneurysms, dissections and tortuosity throughout the arterial tree in association with mild craniofacial features and skeletal and cutaneous anomalies. In contrast with other aneurysm syndromes, most of these affected individuals presented with early-onset osteoarthritis. We mapped the genetic locus to chromosome 15q22.2-24.2 and show that the disease is caused by mutations in SMAD3. This gene encodes a member of the TGF-β pathway that is essential for TGF-β signal transmission. SMAD3 mutations lead to increased aortic expression of several key players in the TGF-β pathway, including SMAD3. Molecular diagnosis will allow early and reliable identification of cases and relatives at risk for major cardiovascular complications. Our findings endorse the TGF-β pathway as the primary pharmacological target for the development of new treatments for aortic aneurysms and osteoarthritis.

A mutation in the acyl-coenzyme A binding domain-containing protein 5 gene (ACBD5) identified in autosomal dominant thrombocytopenia (Article)

2010-09-01T00:00:00Z

Mucopolysaccharidosis type IIID: 12 new patients and 15 novel mutations (Article)

2010-05-01T00:00:00Z

Mucopolysaccharidosis III D (Sanfilippo disease type D, MPS IIID) is a rare autosomal recessive lysosomal storage disorder previously described in only 20 patients. MPS IIID is caused by a deficiency of N-acetylglucosamine-6-sulphate sulphatase (GNS), one of the enzymes required for the degradation of heparan sulphate. So far only seven mutations in the GNS gene have been reported. The clinical phenotype of 12 new MPS IIID patients from 10 families was studied. Mutation analysis of GNS was performed in 16 patients (14 index cases). Clinical signs and symptoms of the MPS IIID patients appeared to be similar to previously described patients with MPS III. Early development was normal with onset of behavioral problems around the age of 4 years, followed by developmental stagnation, deterioration of verbal communication and subsequent deterioration of motor functions. Sequence analysis of the coding regions of the gene encoding GNS (GNS) resulted in the identification of 15 novel mutations: 3 missense mutations, 1 nonsense mutation, 4 splice site mutations, 3 frame shift mutations, 3 large deletions and 1 inframe small deletion. They include the first missense mutations and a relatively high proportion of large rearrangements, which warrants the inclusion of quantitative techniques in routine mutation screening of the GNS gene.

Genome-wide linkage analysis in a Dutch multigenerational family with attention deficit hyperactivity disorder (Article)

2010-02-01T00:00:00Z

Abstract: Attention deficit hyperactivity disorder (ADHD) is a common neuropsychiatric disorder. Genetics has an important role in the aetiology of this disease. In this study, we describe the clinical findings in a Dutch family with eight patients suffering from ADHD, in whom five had at least one other psychiatric disorder. We performed a genome-wide (parametric and nonparametric) affected-only linkage analysis. Two genomic regions on chromosomes 7 and 14 showed an excess of allele sharing among the definitely affected members of the family with suggestive LOD scores (2.1 and 2.08). Nonparametric linkage analyses (NPL) yielded a maxNPL of 2.92 (P=0.001) for marker D7S502 and a maxNPL score of 2.56 (P=0.003) for marker D14S275. We confirmed that all patients share the same haplotype in each region of 7p15.1-q31.33 and 14q11.2-q22.3. Interestingly, both loci have been reported before in Dutch (affected sib pairs) and German (extended families) ADHD linkage studies. Hopefully, the genome-wide association studies in ADHD will help to highlight specific polymorphisms and genes within the broad areas detected by our, as well as other, linkage studies.

First locus for primary pulmonary vein stenosis maps to chromosome 2q (Article)

2009-10-01T00:00:00Z

AimsPrimary pulmonary vein stenosis (PVS) is a rare cardiac abnormality that exhibits a high morbidity and mortality rate. The disease is characterized by obstruction of the pulmonary venous blood flow owing to congenital hypoplasia of individual extra-pulmonary veins. We describe a consanguineous Turkish family with four affected siblings with primary PVS in association with prenatal lymphatic abnormalities. We aimed to map the first gene for primary PVS.Methods and resultsPatients had extensive cardiological examinations including electrocardiograms, echocardiograms, ventilation-perfusion scans, and cardiac catheterizations. All patients died before the age of 16 months because of severe progressive primary PVS. Chromosomal analysis revealed normal karyotypes. We performed a genome-wide linkage analysis using 250 K single nucleotide polymorphism arrays and found the first locus for primary PVS on chromosome 2q35-2q36.1 [multipoint logarithms (base 10) of odds (LOD) scores 3.6]. By fine-mapping with microsatellite markers, we confirmed the homozygous region that extended 6.6 Mb (D2S164-D2S133). Sequencing 12 (188 exons) of the 88 genes from the region revealed no disease-causing sequence variations.ConclusionOur findings open perspectives for the identification of the genetic cause(s) leading to PVS, which might contribute to elucidate the pathological mechanisms involved in this disorder.

Premature ovarian failure and gene polymorphisms (Article)

2009-08-01T00:00:00Z

PURPOSE OF REVIEW: Premature ovarian insufficiency (POI) is a common disorder affecting approximately 1% of women under the age of 40 years. Until now, research aiming to identify genetic causes of POI was mostly based on candidate gene approaches. Recently, several genes have been identified using this approach, and genome-wide searches were conducted. In this review, we discuss these studies and propose future direction for further research in this field. RECENT FINDINGS: Candidate gene approach revealed NOBOX, NR5A1, FIGLA and PGRMC1 as POI-genes. Genome-wide searches (linkage and association studies) are revealing new loci/genes as well. SUMMARY: The role in POI for most reported candidate genes is still under discussion. Because POI families with several affected cases are rare, linkage studies are difficult to conduct; however, the reported loci needs further exploration/replication. In the only genome-wide association studies conducted, the patient cohort used is very small and the reported results are awaiting replication. Unravelling the genetics of POI will need the establishment of a large international consortium.

Mutation in the AP4M1 Gene Provides a Model for Neuroaxonal Injury in Cerebral Palsy (Article)

2009-07-10T00:00:00Z

Cerebral palsy due to perinatal injury to cerebral white matter is usually not caused by genetic mutations, but by ischemia and/or inflammation. Here, we describe an autosomal-recessive type of tetraplegic cerebral palsy with mental retardation, reduction of cerebral white matter, and atrophy of the cerebellum in an inbred sibship. The phenotype was recorded and evolution followed for over 20 years. Brain lesions were studied by diffusion tensor MR tractography. Homozygosity mapping with SNPs was performed for identification of the chromosomal locus for the disease. In the 14 Mb candidate region on chromosome 7q22, RNA expression profiling was used for selecting among the 203 genes in the area. In postmortem brain tissue available from one patient, histology and immunohistochemistry were performed. Disease course and imaging were mostly reminiscent of hypoxic-ischemic tetraplegic cerebral palsy, with neuroaxonal degeneration and white matter loss. In all five patients, a donor splice site pathogenic mutation in intron 14 of the AP4M1 gene (c.1137+1G→T), was identified. AP4M1, encoding for the μ subunit of the adaptor protein complex-4, is involved in intracellular trafficking of glutamate receptors. Aberrant GluRδ2 glutamate receptor localization and dendritic spine morphology were observed in the postmortem brain specimen. This disease entity, which we refer to as congenital spastic tetraplegia (CST), is therefore a genetic model for congenital cerebral palsy with evidence for neuroaxonal damage and glutamate receptor abnormality, mimicking perinatally acquired hypoxic-ischemic white matter injury.

A novel 16p locus associated with BSCL2 hereditary motor neuronopathy: a genetic modifier? (Article)

2009-04-27T00:00:00Z

We describe the neurological, electrophysiological, and genetic features of autosomal dominant distal hereditary motor neuronopathy (HMN) in a three-generation Dutch family, including 12 patients with distal muscle weakness and atrophy. The severity of disease ranged from disabling muscle weakness to a subclinical phenotype. Neurologic exams of nine patients and nerve conduction studies (NCS) and myography in five endorsed the variable presentations of HMN in this family, including patients with only lower (four), upper (one), or both upper and lower extremities involvement (four). Asymmetrical or strictly unilateral disease was noted in three patients. Three also showed pyramidal features. A genome-wide search combining SNP arrays (250K) with parametric linkage analysis identified a novel locus on chromosome 16p (mLOD = 3.28) spanning 6 Mb (rs6500882-rs7192086). Direct sequencing excluded mutations in the SIMPLE/LITAF gene (mapping to the 16p locus) and identified a pathogenic mutation (p.N88S) in BCLS2 (11q12-q14). All 12 affected relatives had the BSCL2 mutation and the chromosome 16p haplotype and showed features of motor neuron degeneration. One patient had a very mild phenotype with bilateral pes cavus, normal concentric needle electromyography but signs of motor neuron involvement at electrophysiological muscle scan (EMS). Similar EMS abnormalities in addition to abnormal NCS and myography were observed in a clinically unaffected person (carrying only the 16p haplotype). These results expand the clinical spectrum of HMN and suggest a digenic inheritance of HMN in this family with a BSCL2 mutation and a chromosome 16 locus likely contributing to the phenotype.

Autosomal dominant inheritance of cardiac valves anomalies in two families: Extended spectrum of left-ventricular outflow tract obstruction (Article)

2009-02-01T00:00:00Z

Only a limited number of families with clear monogenic inheritance of nonsyndromic forms of congenital valve defects have been described. We describe two multiplex pedigrees with a similar nonsyndromic form of heart valve anomalies that segregate as an autosomal dominant condition. The first family is a three-generation pedigree with 10 family members affected with congenital defects of the cardiac valves, including six patients with aortic stenosis and/or aortic regurgitation. Pulmonary and/or tricuspid valve abnormalities were present in three patients, and ventricular septal defect (VSD) was present in two patients. The second family consists of 11 patients in three generations with aortic valve stenosis in seven patients, defects of the pulmonary valves in two patients, and atrial septal defect (ASD) in two patients. Incomplete penetrance was observed in both families. Although left-ventricular outflow tract obstruction was present in most family members, the co-occurrence with pulmonary valve abnormalities and septal defects in both families is uncommon. These families provide evidence that left-sided obstructive defects and thoracic aortic aneurysm may be accompanied by right-sided defects, and even septal defects. These families might be instrumental in identifying genes involved in cardiac valve morphogenesis and malformation.

A genome-wide linkage scan in a Dutch family identifies a premature ovarian failure susceptibility locus (Article)

2008-12-01T00:00:00Z

BACKGROUND: Premature ovarian failure (POF) is characterized by elevated gonadotrophins and amenorrhea before the age of 40 years and occurs approximately in 1% of women. POF etiology is highly heterogeneous with a wide spectrum of etiological pathogenic mechanisms including genetic causes. These mostly involve numerical, structural or monogenic defects on the X-chromosome. Mutations in a small number of autosomal genes (such as FOXL2 and NOBOX) have been identified as a cause of POF. However, in most cases, the disease underlying mechanisms are largely unknown. METHODS: We performed a genome-wide linkage analysis in a relatively large Dutch family with seven patients suffering from POF, showing a dominant pattern of inheritance. A genome-wide analysis, using 50K single nucleotide polymorphism arrays, was combined with conventional parametric linkage analysis. RESULTS: We identified three genomic regions on chromosomes 5, 14 and 18 yielding suggestive linkage (multipoint LOD score of 2.4 for each region). After inclusion of one elder unaffected family member, only the region on chromosome 5 remains as a putative POF locus. In addition, we investigated a second family (three living patients over three generations) for the regions on chromosome 5, 14 and 18. Haplotype analysis supported only the locus on chromosome 5q14.1-q15. CONCLUSION: We performed the first genome-wide linkage search in familial POF and identified a region on chromosome 5q14.1-q15, which may harbor a novel POF susceptibility gene.

A genome search for primary vesicoureteral reflux shows further evidence for genetic heterogeneity (Article)

2008-04-01T00:00:00Z

Vesicoureteral reflux (VUR) is the most common disease of the urinary tract in children. In order to identify gene(s) involved in this complex disorder, we performed a genome-wide search in a selected sample of 31 patients with primary VUR from eight families originating from southern Italy. Sixteen additional families with 41 patients were included in a second stage. Nonparametric, affected-only linkage analysis identified four genomic areas on chromosomes 1, 3, and 4 (p < 0.05); the best result corresponded to the D3S3681-D3S1569 interval on chromosome 3 (nonparametric linkage score, NPL = 2.75, p = 0.008). This region was then saturated with 26 additional markers, tested in the complete group of 72 patients from 24 families (NPL = 2.01, p = 0.01). We identified a genomic area on 3q22.2-23, where 26 patients from six multiplex families shared overlapping haplotypes. However, we did not find evidence for a common ancestral haplotype. The region on chromosome 1 was delimited to 1p36.2-34.3 (D1S228-D1S255, max. NPL = 1.70, p = 0.03), after additional fine typing. Furthermore, on chromosome 22q11.22-12.3, patients from a single family showed excess allele sharing (NPL = 3.35, p = 0.015). Only the chromosome 3q region has been previously reported in the single genome-wide screening available for primary VUR. Our results suggest the presence of several novel loci for primary VUR, giving further evidence for the genetic heterogeneity of this disorder.

ROBO2 gene variants are associated with familial vesicoureteral reflux (Article)

2008-04-01T00:00:00Z

The SLIT2 receptor ROBO2 plays a key role in the formation of the ureteric bud, and its inactivation in mice leads to supernumerary ureteric bud development, lack of ureter remodeling, and improper insertion of the ureters into the bladder. Recently, two heterozygous ROBO2 missense mutations were identified in two families with primary vesicoureteral reflux occurring in combination with congenital anomalies of the kidney and urinary tract (VUR/CAKUT). This study investigated a possible causal role of ROBO2 gene variants in 95 unrelated patients with primary VUR (n = 78) or VUR/CAKUT. Eighty-two percent of all patients had a family history of genitourinary anomalies. Twenty-four ROBO2 gene variants were identified by direct sequencing of all 26 exons and the exon-intron boundaries. Of these, four led to amino acid substitutions: Gly328Ser, Asn515lle, Asp766Gly, and Arg797Gln. When the families were examined, the missense variants co-segregated with VUR (three families) or VUR/CAKUT (one family). These variants were not found in 190 control subjects, and the affected amino acids have been conserved through evolution. In conclusion, a relatively high frequency of ROBO2 variants (5.1%) was found in familial cases; however, functional studies and validation in other cohorts are warranted. Copyright

A new syndrome with noncompaction cardiomyopathy, bradycardia, pulmonary stenosis, atrial septal defect and heterotaxy with suggestive linkage to chromosome 6p (Article)

2008-01-01T00:00:00Z

We report a three-generation family with nine patients affected by a combination of cardiac abnormalities and left isomerism which, to our knowledge, has not been described before. The cardiac anomalies include non-compaction of the ventricular myocardium, bradycardia, pulmonary valve stenosis, and secundum atrial septal defect. The laterality sequence anomalies include left bronchial isomerism, azygous continuation of the inferior vena cava, polysplenia and intestinal malrotation, all compatible with left isomerism. This new syndrome is inherited in an autosomal dominant pattern. A genome-wide linkage analysis suggested linkage to chromosome 6p24.3-21.2 with a maximum LOD score of 2.7 at marker D6S276. The linkage interval is located between markers D6S470 (telomeric side) and D6S1610 (centromeric side), and overlaps with the linkage interval in another family with heterotaxy reported previously. Taken together, the genomic region could be reduced to 9.4 cM (12 Mb) containing several functional candidate genes for this complex heterotaxy phenotype.

STOX1 gene in pre-eclampsia and intrauterine growth restriction (Article)

2007-09-01T00:00:00Z

The STOX1 gene, identified as a candidate gene for pre-eclampsia in Dutch women, is placentally expressed and subject to imprinting with preferential transmission of the maternal allele. In our study, STOX1-Y153H frequencies were similar in 157 women with pre-eclampsia (65%) and in 157 controls (64%) from the general Dutch population. In an isolated Dutch population, a distortion could not be demonstrated in the transmission of STOX1-Y153H variation from heterozygous mothers to offspring in 50 and 56 families with pregnancies complicated by pre-eclampsia or intrauterine growth restriction, respectively. Our findings do not confirm previous suggestions that STOX1 plays a major role in Dutch women with pre-eclampsia.

Relationship of the Ubiquilin 1 gene with Alzheimer's and Parkinson's disease and cognitive function (Article)

2007-08-31T00:00:00Z

Ubiquilin 1 (UBQLN1) is involved in the ubiquitination machinery, which has been implicated in Alzheimer's disease (AD) as well as Parkinson's disease (PD). A polymorphism in the gene encoding for UBQLN1 has been previously associated with a higher risk of AD. We studied the role of the SNP rs12344615 on the UBQLN 1 gene in AD, PD and cognitive function in a population-based study, the Rotterdam Study, and a family-based study embedded in the genetic research in isolated population (GRIP) program. The Rotterdam Study includes 549 patients with AD and 157 patients with PD. The GRIP program includes a series of 123 patients with AD and a study of 1049 persons who are characterized for cognitive function. Data were analysed using logistic and multiple regression analysis. We found no significant difference in risk of AD or PD by the UBQLN1 SNP rs12344615 in our overall and stratified analyses in the Rotterdam Study. In our family-based study, we did not find evidence for linkage of AD to the region including the UBQLN1 gene. In the family-based study we also failed to detect an effect of this polymorphism on cognitive function. Our results suggest that it is unlikely that the SNP rs12344615 of the UBQLN1 gene is related to the onset of AD, PD or cognitive function.

A genomewide screen for late-onset Alzheimer disease in a genetically isolated Dutch population (Article)

2007-07-01T00:00:00Z

Alzheimer disease (AD) is the most common cause of dementia. We conducted a genome screen of 103 patients with late-onset AD who were ascertained as part of the Genetic Research in Isolated Populations (GRIP) program that is conducted in a recently isolated population from the southwestern area of The Netherlands. All patients and their 170 closely related relatives were genotyped using 402 microsatellite markers. Extensive genealogy information was collected, which resulted in an extremely large and complex pedigree of 4,645 members. The pedigree was split into 35 subpedigrees, to reduce the computational burden of linkage analysis. Simulations aiming to evaluate the effect of pedigree splitting on false-positive probabilities showed that a LOD score of 3.64 corresponds to 5% genomewide type I error. Multipoint analysis revealed four significant and one suggestive linkage peaks. The strongest evidence of linkage was found for chromosome 1q21 (heterogeneity LOD [HLOD] = 5.20 at marker D1S498). Approximately 30 cM upstream of this locus, we found another peak at 1q25 (HLOD = 4.0 at marker D1S218). These two loci are in a previously established linkage region. We also confirmed the AD locus at 10q22-24 (HLOD = 4.15 at marker D10S185). There was significant evidence of linkage of AD to chromosome 3q22-24 (HLOD = 4.44 at marker D3S1569). For chromosome 11q24-25, there was suggestive evidence of linkage (HLOD = 3.29 at marker DI1S1320). We next tested for association between cognitive function and 4,173 single-nucleotide polymorphisms in the linked regions in an independent sample consisting of 197 individuals from the GRIP region. After adjusting for multiple testing, we were able to detect significant associations for cognitive function in four of five AD-linked regions, including the new region on chromosome 3q22-24 and regions 1q25, 10q22-24, and 11q25. With use of cognitive function as an endophenotype of AD, our study indicates the that the RGSL2, RALGPS2, and C1orf49 genes are the potential disease-causing genes at 1q25. Our analysis of chromosome 10q22-24 points to the HTR7, MPHOSPH1, and CYP2C cluster. This is the first genomewide screen that showed significant linkage to chromosome 3q23 markers. For this region, our analysis identified the NMNAT3 and CLSTN2 genes. Our findings confirm linkage to chromosome 11q25. We were unable to confirm SORLI; instead, our analysis points to the OPCML and HNT genes.

Homozygous nonsense mutations in KIAA1279 are associated with malformations of the central and enteric nervous systems (Article)

2005-01-01T00:00:00Z

We identified, by homozygosity mapping, a novel locus on 10q21.3-q22.1 for Goldberg-Shprintzen syndrome (GOSHS) in a consanguineous Moroccan family. Phenotypic features of GOSHS in this inbred family included microcephaly and mental retardation, which are both central nervous system defects, as well as Hirschsprung disease, an enteric nervous system defect. Furthermore, since bilateral generalized polymicogyria was diagnosed in all patients in this family, this feature might also be considered a key feature of the syndrome. We demonstrate that homozygous nonsense mutations in KIAA1279 at 10q22.1, encoding a protein with two tetratrico peptide repeats, underlie this syndromic form of Hirschsprung disease and generalized polymicrogyria, establishing the importance of KIAA1279 in both enteric and central nervous system development.

Angiotensin converting enzyme gene polymorphism and cardiovascular morbidity and mortality: the Rotterdam Study. (Article)

2005-01-01T00:00:00Z

BACKGROUND: Findings on the association between the insertion/deletion (I/D) polymorphism of the angiotensin I-converting enzyme (ACE) gene and cardiovascular morbidity and mortality have been inconsistent. Considering the possible interaction between this polymorphism and smoking, we evaluated the association between ACE I/D polymorphism and myocardial infarction (MI), mortality due to coronary heart disease (CHD), and cardiovascular disease (CVD). METHODS: The study was performed within the Rotterdam Study, a population based cohort study. The ACE I/D polymorphism was determined for 6714 participants and smoking status recorded at baseline. Fatal and non-fatal MIs and mortality events were regularly recorded. Cox proportional hazard analysis was performed separately for current smokers and non-smokers. We used age as the follow up time, presenting age specific survivals. RESULTS: During follow up, 248 MIs and 301 and 482 deaths, respectively, due to CHD and CVD occurred. There were no significant differences between the genotypes as regards MI incidence. Among smokers, there was an increased risk of CHD and CVD mortality in carriers of the DD genotype compared to the II genotype, which diminished at later ages (p<0.01 for gene-age interaction). Subgroup analysis in a younger and older group (based on the median age of 68.2 years) showed a significantly increased risk of CVD mortality in the younger group (hazard ratio = 5.19; 95% confidence interval: 1.15 to 23.42). CONCLUSIONS: This study showed that the ACE I/D polymorphism is not a strong risk factor for MI but its interaction with smoking might play a role in cardiovascular mortality especially at younger ages.

Linkage disequilibrium in young genetically isolated Dutch population (Article)

2004-07-01T00:00:00Z

The design and feasibility of genetic studies of complex diseases are critically dependent on the extent and distribution of linkage disequilibrium (LD) across the genome and between different populations. We have examined genomewide and region-specific LD in a young genetically isolated population identified in the Netherlands by genotyping approximately 800 Short Tandem Repeat markers distributed genomewide across 58 individuals. Several regions were analyzed further using a denser marker map. The permutationcorrected measure of LD was used for analysis. A significant (Po0.0004) relation between LD and genetic distance on a genomewide scale was found. Distance explained 4% of the total LD variation. For finemapping data, distance accounted for a larger proportion of LD variation (up to 39%). A notable similarity in the genomewide distribution of LD was revealed between this population and other young genetically isolated populations from Micronesia and Costa Rica. Our study population and experiment was simulated in silico to confirm our knowledge of the history of the population. High agreement was observed between results of analysis of simulated and empirical data. We conclude that our population shows a high level of LD similar to that demonstrated previously in other young genetic isolates. In Europe, there may be a large number of young genetically isolated populations that are similar in history to ours. In these populations, a similar degree of LD is expected and thus they may be effectively used for linkage or LD mapping.

Chasing Genes in Alzheimers's and Parkinsons's Disease (Doctoral Thesis)

2004-06-09T00:00:00Z

Alzheimer’s disease (AD), the most common type of dementia and Parkinson’s disease (PD), the most common movement disorder are both neurodegenerative adult-onset diseases characterized by progressive loss of specifi c neuronal populations and accumulation of intraneuronal inclusions. The search for genetic and environmental factors that determine the fate of neurons during the ageing process has been a widespread approach in the battle against neurodegenerative disorders. Genetic studies of AD and PD have initially focused on the search for genes involved in the aetiological mechanisms of monogenic forms of these diseases. They later expanded to study hundreds of patients, affected relative-pairs and population-based studies sometimes performed on “special” isolated populations. A growing number of genes (and pathogenic mutations) is being identifi ed that cause or increase the susceptibility to AD and PD. This review discussed the way in which strategies of “gene hunting” have evolved during the last years and the signifi cance of fi nding genes such as the presenilins, α-synuclein, parkin and DJ-1. In addition we discuss possible links between these two neurodegenerative disorders. The clinical, pathological and genetic presentation of AD and PD suggests the involvement of few overlapping, interrelated pathways. Their imbricate features point to a spectrum of neurodegeneration (tauopathies, synucleinopathies, amyloidopathies) that will need further intense investigation to find the missing links.

Polymorphisms in the prion protein gene and in the doppel gene increase susceptibility for Creutzfeldt-Jakob disease (Article)

2004-05-01T00:00:00Z

The prion protein gene (PRNP) plays a central role in the origin of Creutzfeldt-Jakob disease (CJD), but there is growing interest in other polymorphisms that may be involved in CJD. Polymorphisms upstream of PRNP that may modulate the prion protein production as well as polymorphisms in the prion-like doppel gene (PRND) have been studied, with inconsistent findings. We investigated the role of a single-nucleotide polymorphism (SNP 1368) located upstream of PRNP and three polymorphisms in PRND (T26M, P56L and T174M) in CJD. The study included a population-based sample of 52 patients with sporadic CJD and 250 controls. We analysed our data as single markers and haplotypes. Further, we conducted a meta-analysis on PRND T174M comparing the data of the four studies conducted to date. For SNP 1368 and PRNP M129V, we found significant evidence for linkage disequilibrium. No evidence was found for a relation of SNP 1368 to CJD independent of PRNP M129V. We further found a significant increased prevalence of M homozygotes at PRND T174M among sporadic CJD patients, when adjusting the analyses for the other genotypes. In the haplotype analyses, the association was strongest for persons homozygous for PRNP 129M and PRND 174M (odds ratio 4.35, 95% confidence interval 1.05-8.09; P=0.04). The meta-analysis on the PRND T174M polymorphism did not show a consistent effect across studies, raising the question as to whether PRND 174M is causally related to CJD, or whether the PRND allele is in linkage disequilibrium with another polymorphism related to CJD.

A study of gene-environment interaction on the gene for angiotensin converting enzyme: a combined functional and population based approach (Article)

2004-01-01T00:00:00Z

INTRODUCTION: Studies on the role of the insertion/deletion (I/D) polymorphism of the gene coding for angiotensin converting enzyme (ACE) in atherosclerosis have been inconsistent. In a meta-analysis, we recently showed that this relationship is stronger in high risk populations. In this paper, we used a combined functional and population based approach to investigate the gene-environment interaction of the ACE I/D polymorphism in relation to carotid artery wall thickness. METHODS: The study was part of the Rotterdam Study, a prospective population based cohort study. In 5321 subjects, IMT was measured in the carotid arteries by ultrasonography and ACE genotype was determined by size analysis of polymerase chain reaction products. RESULTS: In multiple regression analysis, I/D polymorphism and smoking were the main determinants for plasma ACE activity (r(2) = 0.28). There was a positive association between the D allele of the I/D polymorphism and carotid artery thickness among current smokers (p = 0.03). Subjects carrying only one of the risk factors (smoking or the D allele) did not show significant differences in IMT compared with the non-/former smokers group carrying two II alleles, while carriers of both risk factors had significant higher IMT. The association was not present in non-/former smokers. DISCUSSION: The results provide further evidence that genetic and environmental factors interact in the formation of the arterial lesions. This study shows that large population based studies can be extremely helpful in unravelling the genetic origin of complex diseases such as atherosclerosis.

A novel presenilin 1 mutation (L174M) in a large Cuban family with early onset Alzheimer disease. (Article)

2002-10-01T00:00:00Z

We studied a Cuban family with presenile dementia (autosomal dominant) consisting of 281 members within six generations, the proband descended from a Spanish founder. Mean age at onset was 59 years of age. Memory impairment was the main symptom in all patients, additionally, ischemic episodes were described in 4 (n = 18) patients. Neuropathological examination of brain material (1 patient) revealed neuronal loss, amyloid plaques, and neurofibrillary tangles. Thirty DNA samples were genotyped (regions on chromosome 1, 3, 10, 12, 14, 17, 19, 20, and 21). A maximum Lod score of 3.79 at theta = 0 was obtained for marker D14S43, located in a 9-cM interval in which all patients shared the same haplotype. Sequencing of the PSEN1 gene revealed a heterozygous base substitution, C520A (exon 6), which is predicted to cause an amino acid change from leucine to methionine in the TMIII of the presenilin 1 protein. The mutation was found to co-segregate with the disease phenotype and the associated disease haplotype. The C --> A change was not observed in 80 control chromosomes from the Cuban population. Leucine at position 174 is highly conserved among species and is identical in presenilin 1 and presenilin 2 proteins. We propose the L174 M mutation might lead to an abnormal N-terminal and probably C-terminal fragments and malfunction of the protein complex. In conclusion, we found a novel PSEN1 mutation in a large family with clinical and pathological diagnosis of early onset familial Alzheimer disease, which may be relevant for other Hispanic populations.