Pathogenic deep intronic MTM1 variant activates a pseudo-exon encoding a nonsense codon resulting in severe X-linked myotubular myopathy.
Eur J Hum Genet
; 29(1): 61-66, 2021 01.
Article
em En
| MEDLINE
| ID: mdl-32862205
ABSTRACT
X-linked myotubular myopathy (XLMTM) is a severe congenital myopathy characterised by generalised weakness and respiratory insufficiency. XLMTM is associated with pathogenic variants in MTM1; a gene encoding the lipid phosphatase myotubularin. Whole genome sequencing (WGS) of an exome-negative male proband with severe hypotonia, respiratory insufficiency and centralised nuclei on muscle biopsy identified a deep intronic MTM1 variant NG_008199.1(NM_000252.2)c.1468-577A>G, which strengthened a cryptic 5' splice site (A>G substitution at the +5 position). Muscle RNA sequencing was non-diagnostic due to low read depth. Reverse transcription PCR (RT-PCR) of muscle RNA confirmed the c.1468-577A>G variant activates inclusion of a pseudo-exon encoding a premature stop codon into all detected MTM1 transcripts. Western blot analysis establishes deficiency of myotubularin protein, consistent with the severe XLMTM phenotype. We expand the genotypic spectrum of XLMTM and highlight benefits of screening non-coding regions of MTM1 in male probands with phenotypically concordant XLMTM who remain undiagnosed following exome sequencing.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Códon sem Sentido
/
Miopatias Congênitas Estruturais
/
Proteínas Tirosina Fosfatases não Receptoras
Tipo de estudo:
Prognostic_studies
Limite:
Humans
/
Infant
/
Male
Idioma:
En
Revista:
Eur J Hum Genet
Assunto da revista:
GENETICA MEDICA
Ano de publicação:
2021
Tipo de documento:
Article
País de afiliação:
Austrália