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Manifesting carriers of X-linked myotubular myopathy: Genetic modifiers modulating the phenotype.
Souza, Lucas Santos; Almeida, Camila Freitas; Yamamoto, Guilherme Lopes; Pavanello, Rita de Cássia Mingroni; Gurgel-Giannetti, Juliana; da Costa, Silvia Souza; Anequini, Isabela Pessa; do Carmo, Silvana Amanda; Wang, Jaqueline Yu Ting; Scliar, Marília de Oliveira; Castelli, Erick C; Otto, Paulo Alberto; Zanoteli, Edmar; Vainzof, Mariz.
Afiliação
  • Souza LS; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
  • Almeida CF; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
  • Yamamoto GL; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
  • Pavanello RCM; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
  • Gurgel-Giannetti J; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
  • da Costa SS; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
  • Anequini IP; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
  • do Carmo SA; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
  • Wang JYT; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
  • Scliar MO; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
  • Castelli EC; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
  • Otto PA; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
  • Zanoteli E; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
  • Vainzof M; Human Genome and Stem Cell Research Center (L.S.S., C.F.A., G.L.Y., R.d.C.M.P., S.S.d.C., I.P.A., S.A.d.C., J.Y.T.W., M.d.O.S., P.A.O., M.V.), University of São Paulo; Department of Pediatrics (J.G.-G.), Medical School of Federal University of Minas Gerais, Belo Horizonte; Pathology Department (E.C.
Neurol Genet ; 6(5): e513, 2020 Oct.
Article em En | MEDLINE | ID: mdl-33062893
ABSTRACT

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.

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2020 Tipo de documento: Article

Texto completo: 1 Coleções: 01-internacional Base de dados: MEDLINE Tipo de estudo: Prognostic_studies Idioma: En Ano de publicação: 2020 Tipo de documento: Article