Homozygous and Heterozygous Nuclear Lamin A p.R582C Mutation: Different Lipodystrophic Phenotypes in the Same Kindred

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Montenegro, Jr., Renan Magalhaes ^[1] ; Costa-Riquetto, Aline Dantas ^[2] ; Fernandes, Virginia Oliveira ^[1] ; Dias Rangel Montenegro, Ana Paula ^[1] ; de Santana, Lucas Santos ^[2] ; de Lima Jorge, Alexander Augusto ^[2] ; de Azevedo Souza Karbage, Lia Beatriz ^[1] ; Aguiar, Lindenberg Barbosa ^[1] ; Costa Carvalho, Francisco Herlanio ^[1] ; Teles, Milena Gurgel ^[2] ; d'Alva, Catarina Brasil ^[1]

Afiliação do(s) autor(es)

^[1] Univ Fed Ceara, Brazilian Grp Study Inherited & Acquired Lipodyst, Fac Med, Fortaleza, Ceara - Brazil

^[2] Univ Sao Paulo, Monogen Diabet Grp, Genet Endocrinol Unit LIM25, Hosp Clin, Fac Med, Sao Paulo - Brazil

• Tipo de documento: Artigo Científico
• Fonte: FRONTIERS IN ENDOCRINOLOGY; v. 9, AUG 20 2018.
• Citações Web of Science: 2

Resumo

Background: Dunnigan-type familial partial lipodystrophy (FPLD2) is a rare autosomal dominant disease caused by heterozygous mutations in the LMNA gene that results in regional loss of subcutaneous adipose tissue with onset in puberty. However, a generalized lipodystrophy phenotype has also been associated with heterozygous mutations in this gene, demonstrating the noticeable phenotypic heterogeneity of this disease. Methods: We report and describe clinical and metabolic features of four patients from the same family with the p.R582C LMNA mutation, three homozygous and one in the heterozygous state that present with three distinct lipodystrophic phenotypes. Results: Case description: The proband was a 12-year-old girl who developed severe subcutaneous fat atrophy in limbs and abdomen followed by a remarkable dorsocervical fat accumulation in adulthood along with diabetes at age 23. The proband's sister was a phenotypically normal girl who developed hypertriglyceridemia at age 8, progressive features of partial lipodystrophy at age 11, and diabetes at age 22. The proband's mother was first examined at age 32, presenting diabetes and a severe generalized lipodystrophic phenotype; she developed kidney failure at age 41 and died due to diabetic complications. The proband's father was a 50-year-old man with abdominal fat concentration that was initially considered phenotypically normal. Massively parallel sequencing using a platform of genes related to genetic lipodystrophies, followed by Sanger sequencing, revealed the transversion c.1744C>T at exon 11 of the LMNA gene (p.R582C) in the homozygous (mother and daughters) and heterozygous (father) states. Conclusion: We documented three distinct phenotypes of the homozygous and heterozygous p. R582C LMNA mutation in the same kindred, illustrating that FPLD2 linked to mutations in this gene is a disease of great clinical heterogeneity, possibly due to associated environmental or genetic factors. (AU)

• Processo FAPESP: 13/02162-8 - Patogênese molecular e caracterização de doenças monogênicas do desenvolvimento: um caminho para a medicina translacional
• Beneficiário: Berenice Bilharinho de Mendonça
• Modalidade de apoio: Auxílio à Pesquisa - Temático
• Processo FAPESP: 13/19920-2 - Estudo genético-molecular por sequenciamento de nova geração de pacientes com diagnóstico clínico de MODY (Maturity onset diabetes of the Young)
• Beneficiário: Milena Gurgel Teles Bezerra
• Modalidade de apoio: Auxílio à Pesquisa - Regular