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HGNC Approved Gene Symbol: INHBB
Cytogenetic location: 2q14.2 Genomic coordinates (GRCh38): 2:120,346,136-120,351,803 (from NCBI)
The activins, dimers of beta-A or beta-B subunits encoded by the genes Inhba (147290) and Inhbb, respectively, are TGF-beta (see 190180) superfamily members that have roles in reproduction and development (Brown et al., 2000).
Activin ligands act as growth and differentiation factors in many cells and tissues. Mellor et al. (2000) examined the localization of and dimerization among activin subunits. The results demonstrated that activin beta-C (see 601233) can form dimers with activin beta-A and beta-B in vitro, but not with the inhibin alpha subunit (147380). Using a specific antibody, activin beta-C protein was localized to human liver and prostate and colocalized with beta-A and beta-B subunits to specific cell types in benign and malignant prostate tissues. The capacity to form novel activin heterodimers (but not inhibin C) appears to reside in the human liver and prostate. The authors concluded that formation of activin AC or BC heterodimers may have significant implications in the regulation of levels and/or biologic activity of other activins in these tissues.
Malignancy of pheochromocytomas is difficult to estimate on the basis of histopathologic features. In a search for new markers to differentiate malignant pheochromocytomas from benign ones, Salmenkivi et al. (2001) tested the value of inhibin/activin subunit expression. Inhibins are heterodimeric glycoproteins consisting of an alpha subunit and either a beta-A or a beta-B subunit. Activins are composed of beta subunits only. Immunohistochemically, inhibin/activin beta-B subunit was strongly positive in the normal adrenal medulla, but the cortex was negative. A striking difference was found in inhibin/activin beta-B expression between benign and malignant pheochromocytomas. The majority of benign adrenal tumors (27 of 30) showed strong or moderate immunoreactivity, whereas all 7 malignant tumors were negative or only weakly positive for inhibin/activin beta-B subunit. Salmenkivi et al. (2001) suggested that inhibin/activin beta-B subunit is expressed in normal adrenal medullary cells. Strong staining was found in most benign adrenal pheochromocytomas, whereas malignant tumors were almost negative. They concluded that loss of inhibin/activin beta-B subunit expression in pheochromocytomas may be used as an indicator of malignant potential.
Inhibin B is secreted by Sertoli cells in pre- and peripubertal boys, and the serum level of inhibin B is considered to reflect Sertoli cell function. Christiansen et al. (2003) investigated the longitudinal changes of inhibin B in a group of patients with Klinefelter syndrome (karyotype 47,XXY) progressing through puberty and compared them to a group of age- and puberty-matched controls. They found normal levels of inhibin B in prepubertal boys with Klinefelter syndrome and controls. In patients with Klinefelter syndrome as well as controls, inhibin B increased progressively before clinical pubertal onset. However, during late puberty in boys with Klinefelter syndrome inhibin B levels decreased gradually to the low/unmeasurable levels observed later in adult Klinefelter syndrome, while remaining unchanged in the controls.
To investigate the secretion of Sertoli and Leydig cell hormones early in life, Lahlou et al. (2004) studied inhibin B and anti-mullerian hormone (AMH; 600957) in 18 infants with a prenatally diagnosed nonmosaic 47,XXY karyotype from birth to 3 years of age. In XXY infants, levels of follicle-stimulating hormone (FSH; see 136530), luteinizing hormone (LH; see 152780), inhibin B, and AMH did not differ from those of controls. Testosterone levels during the first trimester exhibited a physiologic increase but were lower than in controls (P = 0.0001). Significant correlations were found between testosterone and LH (P less than 0.0001), between inhibin B and FSH (P = 0.0011), and between AMH and inhibin B (P = 0.025). In XXY adolescents, AMH and inhibin B were undetectable. The authors concluded that testosterone secretion is impaired in infants with Klinefelter syndrome. By contrast, inhibin B and AMH secretions were not altered, which raised the question of the mechanism(s) governing the decline of Sertoli cell function after puberty.
Lafuse and Zwilling (1993) mapped the Inhbb gene to mouse chromosome 1 by study of recombinant inbred strains.
Schrewe et al. (1994) created mice deficient for activin beta-B by targeted disruption. Inhbb -/- mice complete embryogenesis and are completely viable. Approximately 40% of the homozygous mutant animals are born with open eyes. Histopathologic analysis did not reveal any abnormalities in homozygous mutant animals other than incompletely penetrant eye defects. Both male and female homozygous mutant animals were fertile.
Matzuk et al. (1995) generated mice with mutations either in activin beta-A or in both activin beta-A and activin beta-B. Activin beta-A-deficient mice developed to term but died within 24 hours of birth. They lacked whiskers and lower incisors and had defects in their secondary palates, including cleft palate, demonstrating that activin beta-A must have a role during craniofacial development. Mice lacking both activin subunits showed the defects in both individual mutants but no additional defects, indicating that there is no functional redundancy between these proteins during embryogenesis.
Whereas mice homozygous for the Inhba-null allele demonstrate disruption of whisker, palate, and tooth development leading to neonatal lethality, homozygous Inhbb-null mice are viable, fertile, and have eye defects. To determine if these phenotypes were due to spatiotemporal expression differences of the ligands or disruption of specific ligand-receptor interactions, Brown et al. (2000) replaced the region of Inhba encoding the mature protein with Inhbb, creating the allele designated Inhba(BK). Although the craniofacial phenotypes of the Inhba-null mutation were rescued by the Inhba(BK) allele, somatic, testicular, genital, and hair growth were grossly affected and influenced by the dosage and bioactivity of the allele. Thus, Brown et al. (2000) concluded that functional compensation within the TGF-beta superfamily can occur if the replacement gene is expressed appropriately. The novel phenotypes in these mice further illustrate the usefulness of insertion strategies for defining protein function. The structural organization of the testes of adult Inhba(BK/BK) mice was normal; however, the differentiation of the seminiferous tubules of Inhba(BK/-) mice was delayed. The testicular volumes of both Inhba(BK/BK) and Inhba(BK/-) mice were less than those of controls, and the dosage of the Inhba(BK) allele correlated positively with testicular size. Inhba(+/BK) males had normal onset of fertility, whereas Inhba(BK/BK) males had delayed onset of fertility similar to Acvr2 (102581) -/- mice. Only 1 in 6 Inhba(BK/BK) females produced litters, whereas Inhba(+/BK) females were normally fertile. The ovaries of Inhba(BK/-) mice were smaller and contained fewer large preantral follicles than those of controls. Inhba(BK/BK) and Inhba(BK/-) mice were identified by their smaller size, slower hair growth, the rough appearance of their fur, and sunken eyes. Approximately 50% of Inhba(BK/BK) mice died by 26 weeks, whereas Inhba(BK/-) mice invariably became cachectic and died between 3 and 4 weeks. The summary of phenotypic findings of Inhba(BK/-) mice includes short whiskers, normal tooth development, no cleft palate, symmetric growth deficiency (severe), enlargement of external genitalia, hypogonadism (severe), delayed hair growth (moderate), hypoglycemia (mild), decreased life expectancy (severe), and anemia.
Bertolino et al. (2008) found that both Alk7 (ACVR1C; 608981) -/- mice and activin B -/- mice developed indistinguishable age-dependent hyperinsulinemia. The effects of Alk7 and activin B deletion on serum insulin (INS; 176730) levels were not additive, suggesting that activin B and ALK7 function in a common pathway to regulate insulin secretion.
Bertolino, P., Holmberg, R., Reissmann, E., Andersson, O., Berggren, P.-O., Ibanez, C. F. Activin B receptor ALK7 is a negative regulator of pancreatic beta-cell function. Proc. Nat. Acad. Sci. 105: 7246-7251, 2008. [PubMed: 18480258] [Full Text: https://doi.org/10.1073/pnas.0801285105]
Brown, C. W., Houston-Hawkins, D. E., Woodruff, T. K., Matzuk, M. M. Insertion of Inhbb into the Inhba locus rescues the Inhba-null phenotype and reveals new activin functions. Nature Genet. 25: 453-457, 2000. [PubMed: 10932194] [Full Text: https://doi.org/10.1038/78161]
Christiansen, P., Andersson, A.-M., Skakkebaek, N. E. Longitudinal studies of inhibin B levels in boys and young adults with Klinefelter syndrome. J. Clin. Endocr. Metab. 88: 888-891, 2003. [PubMed: 12574229] [Full Text: https://doi.org/10.1210/jc.2002-021379]
Lafuse, W. P., Zwilling, B. S. Localization of the inhibin beta-B gene on mouse chromosome 1. Mammalian Genome 4: 399-400, 1993. [PubMed: 8358176] [Full Text: https://doi.org/10.1007/BF00360594]
Lahlou, N., Fennoy, I., Carel, J.-C., Roger, M. Inhibin B and anti-mullerian hormone, but not testosterone levels, are normal in infants with nonmosaic Klinefelter syndrome. J. Clin. Endocr. Metab. 89: 1864-1868, 2004. [PubMed: 15070957] [Full Text: https://doi.org/10.1210/jc.2003-031624]
Matzuk, M. M., Kumar, T. R., Vassalli, A., Bickenbach, J. R., Roop, D. R., Jaenisch, R., Bradley, A. Functional analysis of activins during mammalian development. Nature 374: 354-356, 1995. [PubMed: 7885473] [Full Text: https://doi.org/10.1038/374354a0]
Mellor, S. L., Cranfield, M., Ries, R., Pedersen, J., Cancilla, B., de Kretser, D., Groome, N. P., Mason, A. J., Risbridger, G. P. Localization of activin beta(A)-, beta(B)-, and beta(C)-subunits in human prostate and evidence for formation of new activin heterodimers of beta(C)-subunit. J. Clin. Endocr. Metab. 85: 4851-4858, 2000. [PubMed: 11134153] [Full Text: https://doi.org/10.1210/jcem.85.12.7052]
Salmenkivi, K., Arola, J., Voutilainen, R., Ilvesmaki, V., Haglund, C., Kahri, A. I., Heikkila, P., Liu, J. Inhibin/activin beta-B-subunit expression in pheochromocytomas favors benign diagnosis. J. Clin. Endocr. Metab. 86: 2231-2235, 2001. [PubMed: 11344232] [Full Text: https://doi.org/10.1210/jcem.86.5.7446]
Schrewe, H., Gendron-Maguire, M., Harbison, M. L., Gridley, T. Mice homozygous for a null mutation of activin beta B are viable and fertile. Mech. Dev. 47: 43-51, 1994. [PubMed: 7947320] [Full Text: https://doi.org/10.1016/0925-4773(94)90094-9]