Sultan, C.

A new LH receptor splice mutation responsible for male hypogonadism with subnormal sperm production in the propositus, and infertility with regular cycles in an affected sister (Article)

2008-08-01T00:00:00Z

BACKGROUND: Inactivating LH receptor (LHR) mutations have been described so far in men as well as in women. Phenotypes in men have been variable with in nearly all cases impairment of sex differentiation or azoospermia. We report a milder reproductive phenotype both in a male patient and his sister. METHODS AND RESULTS: We describe a family that carries a homozygous mutation G→A at position -1 at the intron 10-exon 11 boundary of the LHR gene. The male patient presented with delayed puberty, micropenis and oligospermia. Two of his sisters were homozygous for the same mutation and were infertile. Surprisingly, one of them was found to have had regular ovarian cycles for years and showed normal LH values (6.5 and 10.6 mIU/ml for LH and FSH, respectively). In vitro analysis showed that this altered splicing resulted in an LHR from which eight amino acids are deleted from the extracellular domain (ΔTyr317- Ser324). In vitro expression has shown that the receptor was expressed and capable of LH-induced signaling, albeit with reduced potency (P < 0.001). CONCLUSIONS: LHR mutations may represent an underestimated cause of infertility in women, in addition to being responsible for male hypogonadism with reduced spermatogenesis.

Management of infertility in a patient presenting with ovarian dysfunction and McCune-Albright syndrome (Article)

2004-01-01T00:00:00Z

Persistent autonomous ovarian dysfunction in McCune-Albright syndrome (MAS) patients is associated with the development of multiple dominant follicles, premature luteinization, cyst formation, and anovulatory infertility. Due to the mosaic distribution of the mutation, ovaries may be unequally affected. In the current patient, the least affected ovary became quiescent upon GnRH agonist-induced gonadotropin suppression. Normoovulatory cycles were restored after subsequent removal of the affected right ovary, and a pregnancy was established within 3 months. A healthy unaffected girl was born at term after an uneventful pregnancy. The placental tissue was normal, and the mutation was not detected in the placenta, umbilical cord structures, or umbilical cord blood. GnRH analog administration may help to identify those MAS patients who might benefit from unilateral ovariectomy. Because a healthy baby was born, evidence is provided suggesting that MAS is not passed on to the children from the parents.

Dynamics of ovarian function in an adult woman with McCune--Albright syndrome (Article)

2001-01-01T00:00:00Z

Substitution of Ala564 in the first zinc cluster of the deoxyribonucleic acid (DNA)-binding domain of the androgen receptor by Asp, Asn, or Leu exerts differential effects on DNA binding (Article)

1998-01-01T00:00:00Z

In the androgen receptor of a patient with androgen insensitivity, the alanine residue at position 564 in the first zinc cluster of the DNA-binding domain was substituted by aspartic acid. In other members of the steroid receptor family, either valine or alanine is present at the corresponding position, suggesting the importance of a neutral amino acid residue at this site. The mutant receptor was transcriptionally inactive, which corresponded to the absence of specific DNA binding in gel retardation assays, and its inactivity in a promoter interference assay. Two other receptor mutants with a mutation at this same position were created to study the role of position 564 in the human androgen receptor on DNA binding in more detail. Introduction of asparagine at position 564 resulted in transcription activation of a mouse mammary tumor virus promoter, although at a lower level compared with the wild-type receptor. Transcription activation of an (ARE)2-TATA promoter was low, and binding to different hormone response elements could not be visualized. The receptor with a leucine residue at position 564 was as active as the wild-type receptor on a mouse mammary tumor virus promoter and an (ARE)2-TATA promoter, but interacted differentially with several hormone response elements in a gel retardation assay. The results of the transcription activation and DNA binding studies could partially be predicted from three-dimensional modeling data. The phenotype of the patient was explained by the negative charge, introduced at position 564.