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Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum

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Developmental Endocrinology Unit, Laboratory of Hormones and Molecular Genetics LIM/42, Division of Endocrinology, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (FMUSP), Av Dr Eneas de Carvalho Aguiar, 155, 2 Andar, Bloco 6, São Paulo 05403-000, Brazil
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Laboratorio de Sequenciamento em Larga Escala (SELA), Faculdade de Medicina FMUSP, Universidade de São Paulo, São Paulo 01246-903, Brazil
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Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109-5618, USA
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Genetic Endocrinology Unit (LIM25), Division of Endocrinology, Hospital das Clinicas da Faculdade de Medicina da Universidade de São Paulo (FMUSP), São Paulo 01246-903, Brazil
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Authors to whom correspondence should be addressed.
Academic Editor: Mara Giordano
Genes 2021, 12(8), 1128; https://doi.org/10.3390/genes12081128
Received: 17 May 2021 / Revised: 6 July 2021 / Accepted: 15 July 2021 / Published: 25 July 2021
(This article belongs to the Special Issue Novel Genetic causes of Pitutary Hormone Deficiency)
We report four allelic variants (three novel) in three genes previously established as causal for hypopituitarism or related disorders. A novel homozygous variant in the growth hormone gene, GH1 c.171delT (p.Phe 57Leufs*43), was found in a male patient with severe isolated growth hormone deficiency (IGHD) born to consanguineous parents. A hemizygous SOX3 allelic variant (p.Met304Ile) was found in a male patient with IGHD and hypoplastic anterior pituitary. YASARA, a tool to evaluate protein stability, suggests that p.Met304Ile destabilizes the SOX3 protein (ΔΔG = 2.49 kcal/mol). A rare, heterozygous missense variant in the TALE homeobox protein gene, TGIF1 (c.268C>T:p.Arg90Cys) was found in a patient with combined pituitary hormone deficiency (CPHD), diabetes insipidus, and syndromic features of holoprosencephaly (HPE). This variant was previously reported in a patient with severe holoprosencephaly and shown to affect TGIF1 function. A novel heterozygous TGIF1 variant (c.82T>C:p.Ser28Pro) was identified in a patient with CPHD, pituitary aplasia and ectopic posterior lobe. Both TGIF1 variants have an autosomal dominant pattern of inheritance with incomplete penetrance. In conclusion, we have found allelic variants in three genes in hypopituitarism patients. We discuss these variants and associated patient phenotypes in relation to previously reported variants in these genes, expanding our knowledge of the phenotypic spectrum in patient populations. View Full-Text
Keywords: GH1; SOX3; TGIF1; hypopituitarism; allelic variants GH1; SOX3; TGIF1; hypopituitarism; allelic variants
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MDPI and ACS Style

Nakaguma, M.; Ferreira, N.G.B.P.; Benedetti, A.F.F.; Madi, M.C.; Silva, J.M.; Li, J.Z.; Ma, Q.; Bilge Ozel, A.; Fang, Q.; Narcizo, A.d.M.; Cardoso, L.C.; Montenegro, L.R.; Funari, M.F.d.A.; Nishi, M.Y.; Arnhold, I.J.P.; Jorge, A.A.d.L.; Mendonca, B.B.d.; Camper, S.A.; Carvalho, L.R. Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum. Genes 2021, 12, 1128. https://doi.org/10.3390/genes12081128

AMA Style

Nakaguma M, Ferreira NGBP, Benedetti AFF, Madi MC, Silva JM, Li JZ, Ma Q, Bilge Ozel A, Fang Q, Narcizo AdM, Cardoso LC, Montenegro LR, Funari MFdA, Nishi MY, Arnhold IJP, Jorge AAdL, Mendonca BBd, Camper SA, Carvalho LR. Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum. Genes. 2021; 12(8):1128. https://doi.org/10.3390/genes12081128

Chicago/Turabian Style

Nakaguma, Marilena, Nathalia G.B.P. Ferreira, Anna F.F. Benedetti, Mariana C. Madi, Juliana M. Silva, Jun Z. Li, Qianyi Ma, Ayse Bilge Ozel, Qing Fang, Amanda d.M. Narcizo, Laís C. Cardoso, Luciana R. Montenegro, Mariana F.d.A. Funari, Mirian Y. Nishi, Ivo J.P. Arnhold, Alexander A.d.L. Jorge, Berenice B.d. Mendonca, Sally A. Camper, and Luciani R. Carvalho 2021. "Allelic Variants in Established Hypopituitarism Genes Expand Our Knowledge of the Phenotypic Spectrum" Genes 12, no. 8: 1128. https://doi.org/10.3390/genes12081128

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