Manifesting carriers of X-linked myotubular myopathy Genetic modifiers modulating the phenotype

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art_SOUZA_Manifesting_carriers_of_Xlinked_myotubular_myopathy_Genetic_modifiers_2020.PDF.pdf (305.06 KB)
Citações na Scopus
6
Tipo de produção
article
Data de publicação
2020
DOI
Scopus
Web of Science
PubMed
Título da Revista
ISSN da Revista
Título do Volume
Editora
LIPPINCOTT WILLIAMS & WILKINS
Autores
SOUZA, Lucas Santos
ALMEIDA, Camila Freitas
PAVANELLO, Rita de Cassia Mingroni
GURGEL-GIANNETTI, Juliana
COSTA, Silvia Souza da
ANEQUINI, Isabela Pessa
CARMO, Silvana Amanda do
WANG, Jaqueline Yu Ting
SCLIAR, Marilia de Oliveira
Citação
NEUROLOGY-GENETICS, v.6, n.5, article ID e513, 9p, 2020
Projetos de Pesquisa
Unidades Organizacionais
Fascículo
Resumo
Objective To analyze the modulation of the phenotype in manifesting carriers of recessive X-linked myotubular myopathy (XLMTM), searching for possible genetic modifiers. Methods Twelve Brazilian families with XLMTM were molecularly and clinically evaluated. In 2 families, 4 of 6 and 2 of 5 manifesting female carriers were identified. These females were studied for X chromosome inactivation. In addition, whole-exome sequencing was performed, looking for possible modifier variants. We also determined the penetrance rate among carriers of the mutations responsible for the condition. Results Mutations in the MTM1 gene were identified in all index patients from the 12 families, being 4 of them novel. In the heterozygotes, X chromosome inactivation was random in 3 of 4 informative manifesting carriers. The disease penetrance rate was estimated to be 30%, compatible with incomplete penetrance. Exome comparative analyses identified variants within a segment of 4.2 Mb on chromosome 19, containing the killer cell immunoglobulin-like receptor cluster of genes that were present in all nonmanifesting carriers and absent in all manifesting carriers. We hypothesized that these killer cell immunoglobulin-like receptor variants may modulate the phenotype, acting as a protective factor in the nonmanifesting carriers. Conclusions Affected XLMTM female carriers have been described with a surprisingly high frequency for a recessive X-linked disease, raising the question about the pattern of inheritance or the role of modifier factors acting on the disease phenotype. We demonstrated the possible existence of genetic mechanisms and variants accountable for the clinical manifestation in these women, which can become future targets for therapies.
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URI
https://observatorio.fm.usp.br/handle/OPI/38389
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Coleções
Artigos e Materiais de Revistas Científicas - FM/MNE
Artigos e Materiais de Revistas Científicas - HC/ICHC
Artigos e Materiais de Revistas Científicas - HC/ICr
Artigos e Materiais de Revistas Científicas - LIM/15
Artigos e Materiais de Revistas Científicas - LIM/36