HGNC Approved Gene Symbol: INHA
Cytogenetic location: 2q35 Genomic coordinates (GRCh38): 2:219,572,310-219,575,711 (from NCBI)
Bremner (1989) stated that inhibin, a gonadal glycoprotein hormone which regulates pituitary FSH (136530) secretion, was postulated to exist in the 1920s and named in 1932, but 'during the next 40 years...attained only slightly more scientific credibility than the unicorn.' Inhibin exists in 2 forms, each of which shares the same alpha subunit and, when covalently linked to 1 of 2 distinct subunits called beta-a (INHBA; 147290) and beta-b (INHBB; 147390), strongly inhibits pituitary FSH secretion. On the other hand, the dimers of 2 beta subunits, termed activin, are potent stimulators of FSH secretion and release in vitro. These beta subunits share extensive sequence homology with transforming growth factor-beta (190180).
Mason et al. (1986) isolated cDNAs for the 3 inhibin subunits.
Barton et al. (1987, 1989) used cDNAs for the 3 inhibin subunits isolated by Mason et al. (1986) to map cognate loci in mouse and man by Southern blot analysis of somatic cell hybrid DNAs. These experiments demonstrated that INHA maps to 2q33-qter, INHBA to 7p15-p13, and INHBB to 2cen-q13. In the mouse the 2 loci that are on chromosome 2 in man mapped to chromosome 1 and the INHBA gene mapped to mouse chromosome 13. The region of mouse chromosome 1 that carries other genes known to have homologs on human chromosome 2q includes the jsd (juvenile spermatogonial depletion) locus. Adult jsd/jsd mice have elevated levels of serum FSH in their testes and are devoid of spermatogonial cells. The possibility that the mutation in jsd involves the INHA or INHBB gene was investigated by Southern blotting of DNA from jsd/jsd mice and no major deletions or rearrangements were detected (Barton et al., 1989).
Ramasharma and Li (1987) reported the identification and characterization of binding sites for alpha-inhibin on human pituitary membranes.
By S1-nuclease analysis, Meunier et al. (1988) showed that the inhibin subunits are expressed in many extragonadal tissues as well as gonadal tissues, suggesting diverse functions.
Inhibin is normally produced by ovarian granulosa cells. Lappohn et al. (1989) found that inhibin is produced also by granulosa-cell tumors and that measurement of serum inhibin levels is a useful early marker for primary, recurrent, and residual granulosa-cell tumors. The other clinical application that has been explored is male contraception through FSH suppression.
Mellor et al. (1998) studied inhibin alpha-subunit gene and protein expression in prostate cancer. The authors studied mRNA expression by in situ hybridization and protein localization by immunohistochemistry. They observed inhibin alpha-subunit mRNA expression and protein localization in the epithelium of tissues from men with benign prostatic hyperplasia, in regions of basal cell hyperplasia, and in nonmalignant regions of tissue from men with high-grade prostate cancer. In the malignant regions of tissue from men with high-grade prostate cancer, expression of the inhibin alpha-subunit gene was suppressed and was not detectable in poorly differentiated tumor cells. These results indicated that in contrast to ovarian granulosa cell tumors, alpha-inhibin gene expression is downregulated in poorly differentiated prostate cancer.
Schmitt et al. (2002) examined the INHA gene promoter and gene locus to determine whether promoter hypermethylation or loss of heterozygosity (LOH) occurred in DNA from prostate cancer. A 135-bp region of the human promoter sequence that continued a cluster of CpG sites was analyzed for hypermethylation. Significant (p less than 0.001) hypermethylation of the INHA gene promoter occurred in DNA from Gleason pattern 3, 4, and 5 carcinomas compared with nonmalignant tissue samples. A subset of carcinomas with a cribriform pattern were unmethylated. LOH at 2q32-q36, the chromosomal region harboring the INHA gene, was observed in 42% of prostate carcinomas. The authors concluded that these data provided the first demonstration that promoter hypermethylation and LOH are associated with the INHA gene and gene locus in prostate cancer.
Thirunavukarasu et al. (2001) reported that the molecular weight patterns of INHBA and pro-alpha-C (a processed form of the free alpha subunit) in serum during early pregnancy (less than 19 weeks' gestation) showed peaks between 25 and 40 kD and approximately 60 kD, consistent with the presence of known mature and larger precursor inhibin forms. However, during late pregnancy (more than 19 weeks' gestation), an increase in the proportion of smaller molecular weight forms (from 2 to 25%) of INHBA and pro-alpha-C of unknown structure were observed in the less than 30-kD and less than 25-kD regions, respectively. Incubation of iodinated 30-kD human INHBA with serum or plasma obtained from early or late pregnancy showed no evidence of cleavage, suggesting that 30-kD INHBA is not the cleavage precursor. The authors concluded that INHBA and pro-alpha-C are processed in late pregnancy by more than one mechanism to form low molecular weight circulating forms of unknown structure.
Longui et al. (2004) investigated the INHA gene in 46 Brazilian children with adrenocortical tumors (ADCC; 202300), 39 of whom were heterozygous carriers of the R337H TP53 mutation (191170.0035). Six patients were heterozygous for 3 INHA mutations: 127C-G in exon 1 and 3998G-A and 4088G-A in exon 2, leading to P43A, G227R, and A257T substitutions, respectively. A257T is located in a conserved INHA region, highly homologous to transforming growth factor-beta; both G227R and A257T change polarity, and G227R also changes the pH. Longui et al. (2004) concluded that INHA may be one of the contributing factors needed for adrenocortical tumor formation in pediatric patients with the R337H TP53 mutation.
Associations Pending Confirmation
For discussion of a possible association between premature ovarian failure (see 311360) and variation in the INHA gene, see 147380.0001.
Using embryonic stem cell technology, Matzuk et al. (1992) generated inhibin-deficient mice, which developed sex cord stromal tumors at an early age with nearly 100% penetrance, demonstrating that inhibin functions in vivo as a tumor suppressor in the gonads of mice. Matzuk et al. (1994) demonstrated that a severe wasting syndrome, which mimics the human cancer cachexia syndrome, accompanies the development of gonadal sex cord stromal tumors in inhibin-deficient mice. The cachectic inhibin-deficient mice developed hepatocellular necrosis around the central vein and parietal cell depletion and mucosal atrophy in the glandular stomach, were anemic, and demonstrated severe weight loss. Activins were elevated more than 10-fold in the serum. In contrast, inhibin-deficient mice gonadectomized at an early age did not develop this wasting syndrome; however, these mice eventually developed adrenal cortical sex steroidogenic tumors with nearly 100% penetrance, demonstrating that inhibin is also a tumor suppressor for the adrenal gland.
Itman et al. (2015) found that 8-week-old Inha +/- mice had lower testicular and circulating Inha concentrations than wildtype, but that activin and Fsh concentrations were normal. Moreover, they had larger testes, greater daily sperm production, and more efficient spermatogenesis than wildtype. In contrast, 16-day-old Inha +/- mice had a mixed testicular phenotype of extensive germ cell depletion and advanced maturation but no evidence of prolonged Sertoli cell proliferation, and this abnormal phenotype resolved by day 28. By 26 weeks of age, daily sperm production and spermatogenic efficiency declined in Inha +/- mice, with no measurable changes in circulating hormone concentrations but with impaired function of Sertoli and Leydig cells. The authors concluded that a threshold level of Inha was required for normal testis development to sustain adult somatic testicular cell function.
This variant is classified as a variant of unknown significance because there is conflicting evidence regarding its contribution to premature ovarian failure (POF; see 311360).
In 50 New Zealand patients with premature ovarian failure and 20 from Slovenia, Harris et al. (2005) screened for a -16C-T polymorphism in the promoter region of the INHA gene and observed underrepresentation of the T allele in POF patients compared to controls. Analysis of the INHA promoter region revealed that the imperfect TG repeat element was highly polymorphic, and that the shortest repeat (designated haplotype C) was in linkage disequilibrium with -16T. However, no significant differences in promoter activity were observed between haplotype C and 7 other promoter haplotypes, except for 1 (haplotype B) that showed no promoter activity.
In 61 Argentinian women with POF, 18 of whom had a known autoimmune disorder, and 82 controls, Sundblad et al. (2006) analyzed the INHA gene but could not demonstrate an association between the -16C-T variant and the risk of POF. In addition, studying 46 women below the age of 40 with regular menses, the authors found no significant differences in inhibin A, inhibin B, or pro-alpha-C peptide levels between women who were homozygous for CC at -16 or women who carried CT or TT alleles. Sundblad et al. (2006) concluded that the -16C-T variant may not be associated with POF disease.
In 3 independent POF cohorts, consisting of a total of 611 patients and 1,084 matched controls from Italy and Germany, Corre et al. (2009) found no association between the -16C-T variant and POF.
Barton, D. E., Yang-Feng, T. L., Mason, A. J., Seeburg, P. H., Francke, U. INHA, INHBA and INHBB, the loci for the three subunits of inhibin, mapped in mouse and man. (Abstract) Cytogenet. Cell Genet. 46: 578 only, 1987.
Barton, D. E., Yang-Feng, T. L., Mason, A. J., Seeburg, P. H., Francke, U. Mapping of genes for inhibin subunits alpha, beta(A) and beta(B) on human and mouse chromosomes and studies of jsd mice. Genomics 5: 91-99, 1989. [PubMed: 2767687] [Full Text: https://doi.org/10.1016/0888-7543(89)90091-8]
Bremner, W. J. Inhibin: from hypothesis to clinical application. (Editorial) New Eng. J. Med. 321: 826-827, 1989. [PubMed: 2770812] [Full Text: https://doi.org/10.1056/NEJM198909213211210]
Corre, T., Schuettler, J., Bione, S., Marozzi, A., Persani, L., Rossetti, R., Torricelli, F., Giotti, I., Vogt, P., Toniolo, D. A large-scale association study to assess the impact of known variants of the human INHA gene on premature ovarian failure. Hum. Reprod. 24: 2023-2038, 2009. [PubMed: 19363042] [Full Text: https://doi.org/10.1093/humrep/dep090]
Harris, S. E., Chand, A. L., Winship, I. M., Gersak, K., Nishi, Y., Yanase, T., Nawata, H., Shelling, A. N. INHA promoter polymorphisms are associated with premature ovarian failure. Molec. Hum. Reprod. 11: 779-784, 2005. [PubMed: 16390856] [Full Text: https://doi.org/10.1093/molehr/gah219]
Itman, C., Bielanowicz, A., Goh, H., Lee, Q., Fulcher, A. J., Moody, S. C., Doery, J. C., Martin, J., Eyre, S., Hedger, M. P., Loveland, K. L. Murine inhibin alpha-subunit haploinsufficiency causes transient abnormalities in prepubertal testis development followed by adult testicular decline. Endocrinology 156: 2254-2268, 2015. [PubMed: 25781564] [Full Text: https://doi.org/10.1210/en.2014-1555]
Lappohn, R. E., Burger, H. G., Bouma, J., Bangah, M., Krans, M., de Bruijn, H. W. A. Inhibin as a marker for granulosa-cell tumors. New Eng. J. Med. 321: 790-793, 1989. [PubMed: 2770810] [Full Text: https://doi.org/10.1056/NEJM198909213211204]
Longui, C. A., Lemos-Marini, S. H. V., Figueiredo, B., Mendonca, B. B., Castro, M., Liberatore, R., Jr., Watanabe, C., Lancellotti, C. L. P., Rocha, M. N., Melo, M. B., Monte, O., Calliari, L. E. P., and 9 others. Inhibin alpha-subunit (INHA) gene and locus changes in paediatric adrenocortical tumours from TP53 R337H mutation heterozygote carriers. J. Med. Genet. 41: 354-359, 2004. [PubMed: 15121773] [Full Text: https://doi.org/10.1136/jmg.2004.018978]
Mason, A. J., Hayflick, J. S., Ling, N., Esch, F., Ueno, N., Ying, S.-Y., Guillemin, R., Niall, H., Seeburg, P. H. Complementary DNA sequences of ovarian follicular fluid inhibin show precursor structure and homology with transforming growth factor-beta. Nature 318: 659-663, 1985. [PubMed: 2417121] [Full Text: https://doi.org/10.1038/318659a0]
Mason, A. J., Niall, H. D., Seeburg, P. H. Structure of two human ovarian inhibins. Biochem. Biophys. Res. Commun. 135: 957-964, 1986. [PubMed: 3754442] [Full Text: https://doi.org/10.1016/0006-291x(86)91021-1]
Matzuk, M. M., Finegold, M. J., Mather, J. P., Krummen, L., Lu, H., Bradley, A. Development of cancer cachexia-like syndrome and adrenal tumors in inhibin-deficient mice. Proc. Nat. Acad. Sci. 91: 8817-8821, 1994. [PubMed: 8090730] [Full Text: https://doi.org/10.1073/pnas.91.19.8817]
Matzuk, M. M., Finegold, M. J., Su, J.-G. J., Hsueh, A. J. W., Bradley, A. Alpha-inhibin is a tumour-suppressor gene with gonadal specificity in mice. Nature 360: 313-319, 1992. [PubMed: 1448148] [Full Text: https://doi.org/10.1038/360313a0]
Mellor, S. L., Richards, M. G., Pedersen, J. S., Robertson, D. M., Risbridger, G. P. Loss of the expression and localization of inhibin alpha-subunit in high grade prostate cancer. J. Clin. Endocr. Metab. 83: 969-975, 1998. [PubMed: 9506758] [Full Text: https://doi.org/10.1210/jcem.83.3.4640]
Meunier, H., Rivier, C., Evans, R. M., Vale, W. Gonadal and extragonadal expression of inhibin alpha, beta-A and beta-B subunits in various tissues predicts diverse functions. Proc. Nat. Acad. Sci. 85: 247-251, 1988. [PubMed: 2829170] [Full Text: https://doi.org/10.1073/pnas.85.1.247]
Ramasharma, K., Li, C. H. Characteristics of binding of human seminal alpha-inhibin-92 to human pituitary membranes. Proc. Nat. Acad. Sci. 84: 3595-3598, 1987. [PubMed: 3035540] [Full Text: https://doi.org/10.1073/pnas.84.11.3595]
Schmitt, J. F., Millar, D. S., Pedersen, J. S., Clark, S. L., Venter, D. J., Frydenberg, M., Molloy, P. L., Risbridger, G. P. Hypermethylation of the inhibin alpha-subunit gene in prostate carcinoma. Molec. Endocr. 16: 213-220, 2002. [PubMed: 11818495] [Full Text: https://doi.org/10.1210/mend.16.2.0771]
Sundblad, V., Chiauzzi, V. A., Andreone, L., Campo, S., Charreau, E. H., Dain, L. Controversial role of inhibin alpha-subunit gene in the aetiology of premature ovarian failure. Hum. Reprod. 21: 1154-1160, 2006. [PubMed: 16396934] [Full Text: https://doi.org/10.1093/humrep/dei452]
Thirunavukarasu, P., Stephenson, T., Forray, J., Stanton, P. G., Groome, N., Wallace, E., Robertson, D. M. Changes in molecular weight forms of inhibin A and pro-alpha-C in maternal serum during human pregnancy. J. Clin. Endocr. Metab. 86: 5794-5804, 2001. [PubMed: 11739441] [Full Text: https://doi.org/10.1210/jcem.86.12.8094]