Hum. Reprod. Advance Access originally published online on May 27, 2008
Human Reproduction 2008 23(8):1917-1923; doi:10.1093/humrep/den180
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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
1 Department of Internal Medicine, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands 2 Service d'Endocrinologie de la Reproduction, Hôpital Saint-Antoine, Assistance Publique-Hôpitaux de Paris (AP-HP), 75012 Paris, France 3 UPRES 1533, University Paris VI, Paris, France 4 Service d'Hormonologie and Institut National de la Santé et de la Recherche Médicale U540, CHU Montpellier, 34090 Montpellier, France 5 Service d'Histologie-Embryologie, Biologie de la Reproduction, CECOS, Hôpital Cochin, AP-HP, 75014 Paris, France 6 Centre de fertilité, Groupe hospitalier Diaconesses-Croix-Saint-Simon, 75012 Paris, France 7 Laboratoire de biochimie, CHU Nîmes, 30029 Nîmes, France
8 Correspondence address. Tel: +33-1-49-28-24-09; Fax: +33-1-49-28-20-69; E-mail: philippe.bouchard{at}sat.aphp.fr
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 (
Tyr317-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.
Key words: LH receptor/splice mutation/male hypogonadism/menstrual cycle
Submitted on February 6, 2008; resubmitted on April 11, 2008; accepted on April 15, 2008.