ClinVar Genomic variation as it relates to human health

In a healthy woman who was fertile and had normal levels of all other hormones measured, Pettersson et al. (1992) identified an immunologically anomalous form of LH (see HH23, 228300). Later, the immunologic abnormality was found to be due to 2 point mutations in the LHB gene. In 3 Japanese women with infertility, Furui et al. (1994) found the same 2 mutations: codon 8, TGG to CGG; codon 15, ATC to ACC. One of the mutations introduced an extra glycosylation signal to the LH beta chain. This site is glycosylated, as is the case with an identical structure in the chorionic gonadotropin beta chain (CGB; 118860). The mutated LH form would probably differ from normal LH in its biologic behavior. Haavisto et al. (1995) found that the frequency of the aberrant LH form in the Finnish population was 24.1% for heterozygotes and 3.6% for homozygotes, with similar proportions in each sex. The ratio of in vitro bioactivity to immunoreactivity of the variant LH was significantly increased, but no difference was observed in LH pulsatility or in the responses of LH immunoreactivity to GNRH stimulation. Haavisto et al. (1995) speculated that, although the subjects homozygous for the LH polymorphism were apparently healthy, the altered bioactivity and in vivo kinetics may induce subtle changes in LH action, either predisposing affected persons to or protecting them from disease conditions related to LH action. To assess the effect of the trp8-to-arg and ile15-to-thr LH variant on LH action, Raivio et al. (1996) correlated its presence in a group of 49 healthy boys with the onset and progression of puberty. This group was followed-up longitudinally from a mean age of 11.7 +/- 0.1 years for 3 years at 3-month intervals. In addition, they studied the prevalence of the variant in boys with constitutional pubertal delay (testicular volume less than 4 ml after 13.5 years of age). Of the boys with pubertal onset at a normal age, 36 (74%) were homozygous for the wildtype LH-beta allele, 12 (24%) were heterozygous, and 1 (2%) was homozygous for the variant LH-beta allele. Clear differences in pubertal parameters were found between the boys with normal and mutant (homo- or heterozygous) LH genotypes. During follow-up, boys with the trp8-to-arg and ile15-to-thr genotype had smaller testicular volumes (p less than 0.03), were shorter (p less than 0.02), had slower growth rates (p less than 0.04), and had lower serum insulin-like growth factor I-binding protein-3 levels (p less than 0.03) than the boys with the normal LH genotype. Raivio et al. (1996) concluded that during the progression of puberty, the variant LH may be less active than wildtype LH in stimulating testicular growth. Tapanainen et al. (1999) studied the frequency of the trp8-to-arg and ile15-to-thr variant LH allele in groups of polycystic ovary syndrome (PCOS; 184700) patients from Finland, the Netherlands, the U.K., and the U.S. The LH status was determined by 2 immunofluorometric assays from a total of 1,466 subjects. The carrier frequency of the variant LH allele in the whole study population was 18.5%, being highest (28.9%) in Finland and lowest (11.2%) in the Netherlands. In the individual countries, the frequency of the variant LH allele was similar in obese and nonobese controls, but in the Netherlands and Finland, it was 5- to 7-fold lower in obese PCOS subjects compared with the other groups (2 to 4.5% vs 10.3 to 33.3%; P less than 0.05). A similar tendency was found in the U.S. (5.7% vs 11.1 to 25.0%) but not in the U.K. The overall high prevalence of the variant LH allele in healthy women and women with PCOS suggested that it is compatible with fertility. The similar frequency of the variant LH allele in healthy nonobese and obese women indicated that obesity per se is not related to the variant. In contrast, the lower frequency of the variant LH allele in obese PCOS patients suggested that the variant may protect obese women from developing symptomatic PCOS. However, the authors concluded that regional differences in this finding between patients with apparently similar diagnostic criteria emphasizes the multifactorial nature of PCOS, and that its pathogenesis may vary according to genetic background. Van den Beld et al. (1999) studied the correlations between serum LH concentration and the clinical characteristics of frailty and determined the presence and concentration of the trp8-to-arg and ile15-to-thr LH variant. An independently living population of 403 healthy elderly men (aged 73 to 94 years) were randomly selected from a population-based sample. Total testosterone (T), sex hormone-binding globulin (SHBG; 182205), and leptin (164160) were determined by RIA. Non-SHBG-bound T was calculated. LH and the presence of the LH variant were measured using immunofluorometric assays. The characteristics of frailty were leg extensor strength using dynamometry, bone mineral density of total body and proximal femur, and body composition, including lean mass and fat mass, measured by dual energy x-ray absorptiometry. LH significantly increased with age and inversely correlated with T and non-SHBG-bound T. LH was inversely related to muscle strength and lean mass, and both relations were independent of T. LH was positively related to self-reported disability. Of the study population, 12.5% were heterozygous for the LH variant allele. T levels and the degree of frailty were not different in the wildtype LH group compared with those heterozygous for the LH variant. A significant positive relation between LH and fat mass as well as leptin was only present in the heterozygous group. The results indicated that serum LH levels increase with age in independently living elderly men and these levels correlate inversely with a variety of indicators of frailty. The observed relation between LH and frailty, independent of T, suggested that LH reflects serum androgen activity in a different way than T, possibly reflecting more closely the combined feedback effect of estrogen and androgen. A difference in biologic response between the 2 LH forms was suggested, as a difference existed in the relation between LH and fat mass, respectively, and leptin in the subjects heterozygous for the LH variant compared with wildtype LH subjects. Ramanujam et al. (2000) analyzed the LHB gene in 145 infertile and 200 healthy fertile men, and identified the W8R/I15T polymorphism in heterozygosity in 12 infertile and 14 fertile men. In addition, 1 fertile man was homozygous for the variant. The prevalence of W8R/I15T did not differ significantly between fertile and infertile men. In a study of 95 infertile and 200 fertile men from South Korea, Lee et al. (2003) found heterozygosity for W8R/I15T in 12.6% of the infertile and 14.5% of the fertile men. (less)