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Department of BioMedical Research, University of Bern, Bern, Switzerland
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Department of BioMedical Research, University of Bern, Bern, Switzerland
Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
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Department of BioMedical Research, University of Bern, Bern, Switzerland
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Department of BioMedical Research, University of Bern, Bern, Switzerland
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Biallelic variants of steroidogenic acute regulatory protein (STAR/STARD1) may cause primary adrenal insufficiency and 46,XY disorder of sex development. STAR plays a pivotal role in transporting cholesterol into mitochondria where cholesterol serves as an essential substrate for initiating steroid biosynthesis by its conversion to pregnenolone. Generally, loss-of-function mutations of STAR cause the classic form of lipoid congenital adrenal hyperplasia (LCAH) where steroidogenesis of the adrenal cortex and the gonads is severely affected. By contrast, partial activity of STAR causes a less severe phenotype, the non-classic LCAH, which is characterized by later onset and initial manifestation with isolated adrenal insufficiency only. Disease-causing STAR variants are very rare. Numerous variants of all types have been described worldwide. Prevailing variants have been reported from Japan and Korea and in some population clusters where STAR is more common. Genotype–phenotype correlation is pretty good for STAR variants. While the exact mechanisms of cholesterol transport into mitochondria for steroidogenesis are still under investigation, the important role of STAR in this process is evident by inactivating STAR variants causing LCAH. The mechanism of disease with STAR deficiency is best described by a two-hit model: the first hit relates to impaired cholesterol import into mitochondria and thus lack of substrate for all steroid hormone biosynthesis; the second hit then relates to massive cytoplasmic lipid overload (evidenced by typically enlarged and fatty adrenal glands) leading to cell death and organ destruction. This review summarizes phenotype and genotype characteristics of human STAR variants found through the ClinVar database.
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. Egawa S , Futami H, Takasaki K, Iihara M, Okamoto T, Kanbe M, Ohi T, Saio Y, Miyauchi A, Takiyama Y et al. 1998 Genotype-phenotype correlation of patients with multiple endocrine neoplasia type 2 in Japan. Japanese Journal of Clinical Oncology
INSERM, University Paris Descartes, Assistance Publique-Hôpitaux de Paris, UMRS_970, Paris Cardiovascular Research Center – PARCC, 56, rue Leblanc, 75015 Paris, France
INSERM, University Paris Descartes, Assistance Publique-Hôpitaux de Paris, UMRS_970, Paris Cardiovascular Research Center – PARCC, 56, rue Leblanc, 75015 Paris, France
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INSERM, University Paris Descartes, Assistance Publique-Hôpitaux de Paris, UMRS_970, Paris Cardiovascular Research Center – PARCC, 56, rue Leblanc, 75015 Paris, France
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INSERM, University Paris Descartes, Assistance Publique-Hôpitaux de Paris, UMRS_970, Paris Cardiovascular Research Center – PARCC, 56, rue Leblanc, 75015 Paris, France
INSERM, University Paris Descartes, Assistance Publique-Hôpitaux de Paris, UMRS_970, Paris Cardiovascular Research Center – PARCC, 56, rue Leblanc, 75015 Paris, France
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milder phenotypes of families carrying p.Gly151Glu mutations and the absence of adrenal hyperplasia ( Mulatero et al . 2012 , Scholl et al . 2012 ). The notion of a strict genotype–phenotype correlation has however been challenged recently, with the
Department of Medical Biotechnologies, University of Siena, Siena, Italy
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distributed throughout the whole gene. A clear genotype–phenotype correlation has not been demonstrated ( Kouvaraki et al. 2002 , Verges et al. 2002 , Horiuchi et al. 2013 , de Laat et al. 2015 ). Approximately 30–40% of MEN1 patients develop PAs
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:10.1089/105072504322783803 . Lyle R Bena F Gagos S Gehrig C Lopez G Schinzel A Lespinasse J Bottani A Dahoun S Taine L 2009 Genotype–phenotype correlations in Down syndrome identified by array CGH in 30 cases of partial trisomy
Disciplina de Endocrinologia, Departamento de Clínica Médica, Hospital das Clinicas, UNICAMP, Campinas, São Paulo, Brazil
Departamento de Genética Médica, Faculdade de Ciências Médicas, UNICAMP, Campinas, 13083970, São Paulo, Brazil
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Disciplina de Endocrinologia, Departamento de Clínica Médica, Hospital das Clinicas, UNICAMP, Campinas, São Paulo, Brazil
Departamento de Genética Médica, Faculdade de Ciências Médicas, UNICAMP, Campinas, 13083970, São Paulo, Brazil
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Disciplina de Endocrinologia, Departamento de Clínica Médica, Hospital das Clinicas, UNICAMP, Campinas, São Paulo, Brazil
Departamento de Genética Médica, Faculdade de Ciências Médicas, UNICAMP, Campinas, 13083970, São Paulo, Brazil
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Disciplina de Endocrinologia, Departamento de Clínica Médica, Hospital das Clinicas, UNICAMP, Campinas, São Paulo, Brazil
Departamento de Genética Médica, Faculdade de Ciências Médicas, UNICAMP, Campinas, 13083970, São Paulo, Brazil
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Genetics 45 237 –240. Oliveira LM , Seminara SB, Beranova M, Hayes FJ, Valkenburgh SB, Schipani E, Costa EM, Latronico AC, Crowley WF Jr & Vallejo M 2001 The importance of autosomal genes in Kallmann syndrome: genotype-phenotype
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Stanford Diabetes Research Center, Stanford University, Stanford, California, USA
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causing MODY can also be related to NDM, with a strong genotype-phenotype correlation. Of the >80% of NDM cases with a known genetic cause, more than 18 causative genes have been described in the literature but many of these are very rare and only seen in
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within members of the same kindred and no genotype–phenotype correlation has been identified ( Houlden et al . 2002 , Huebner et al . 2002 , Milenkovic et al . 2010 ). The AAAS gene product is the 60 kDa nuclear pore complex (NPC) protein ALADIN
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reported ( Lemos & Thakker 2008 ). The majority (>70%) of these mutations are predicted to lead to truncated forms of menin, although there appears to be an absence of genotype–phenotype correlation ( Lemos & Thakker 2008 ). More than 97% of these MEN1
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nevoid basal cell carcinoma syndrome lead to a premature termination of the PATCHED protein, and no genotype-phenotype correlations are evident . American Journal of Human Genetics 60 21 – 2 6 . Willems C Fu Q Roose H Mertens F Cox B Chen
