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.
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.


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 (Delta Tyr(317)-Ser(324)). 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.
Department of Internal Medicine, Erasmus MC, PO Box 2040, 3000 CA Rotterdam, The Netherlands.
M
M
Bruysters
S
S
Christin-Maitre
M
M
Verhoef-Post
C
C
Sultan
J
J
Auger
I
I
Faugeron
L
L
Larue
S
S
Lumbroso
A P N
AP
Themmen
P
P
Bouchard
D000328:Adult; D017398:Alternative Splicing; D001483:Base Sequence; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007006:Hypogonadism / Q000235:genetics*; D007247:Infertility, Female / Q000235:genetics*; D008297:Male; D008597:Menstrual Cycle / Q000235:genetics; D008875:Middle Aged; D008969:Molecular Sequence Data; D009845:Oligospermia / Q000235:genetics*; D010375:Pedigree; D010413:Penis / Q000002:abnormalities; D011628:Puberty, Delayed / Q000235:genetics; D011974:Receptors, LH / Q000235:genetics*; D014162:Transfection
D011974:Receptors, LH