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A deep intronic variant in MME causes autosomal recessive Charcot-Marie-Tooth neuropathy through aberrant splicing.
Grosz, Bianca R; Parmar, Jevin M; Ellis, Melina; Bryen, Samantha; Simons, Cas; Reis, Andre L M; Stevanovski, Igor; Deveson, Ira W; Nicholson, Garth; Laing, Nigel; Wallis, Mathew; Ravenscroft, Gianina; Kumar, Kishore R; Vucic, Steve; Kennerson, Marina L.
Afiliación
  • Grosz BR; Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales, Australia.
  • Parmar JM; The University of Sydney, Camperdown, New South Wales, Australia.
  • Ellis M; Rare Disease Genetics and Functional Genomics Research Group, Harry Perkins Institute of Medical Research, QEII Medical Centre, Nedlands, Western Australia, Australia.
  • Bryen S; Centre for Medical Research, Faculty of Health and Medical Sciences, The University of Western Australia, Perth, Western Australia, Australia.
  • Simons C; Northcott Neuroscience Laboratory, ANZAC Research Institute, Sydney, New South Wales, Australia.
  • Reis ALM; The University of Sydney, Camperdown, New South Wales, Australia.
  • Stevanovski I; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, New South Wales, Australia.
  • Deveson IW; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
  • Nicholson G; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, New South Wales, Australia.
  • Laing N; Centre for Population Genomics, Murdoch Children's Research Institute, Melbourne, Victoria, Australia.
  • Wallis M; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, New South Wales, Australia.
  • Ravenscroft G; Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
  • Kumar KR; Faculty of Medicine, University of New South Wales, Sydney, New South Wales, Australia.
  • Vucic S; Centre for Population Genomics, Garvan Institute of Medical Research, and UNSW Sydney, Sydney, New South Wales, Australia.
  • Kennerson ML; Genomics and Inherited Disease Program, Garvan Institute of Medical Research, Sydney, New South Wales, Australia.
J Peripher Nerv Syst ; 29(2): 262-274, 2024 Jun.
Article en En | MEDLINE | ID: mdl-38860315
ABSTRACT

BACKGROUND:

Loss-of-function variants in MME (membrane metalloendopeptidase) are a known cause of recessive Charcot-Marie-Tooth Neuropathy (CMT). A deep intronic variant, MME c.1188+428A>G (NM_000902.5), was identified through whole genome sequencing (WGS) of two Australian families with recessive inheritance of axonal CMT using the seqr platform. MME c.1188+428A>G was detected in a homozygous state in Family 1, and in a compound heterozygous state with a known pathogenic MME variant (c.467del; p.Pro156Leufs*14) in Family 2.

AIMS:

We aimed to determine the pathogenicity of the MME c.1188+428A>G variant through segregation and splicing analysis.

METHODS:

The splicing impact of the deep intronic MME variant c.1188+428A>G was assessed using an in vitro exon-trapping assay.

RESULTS:

The exon-trapping assay demonstrated that the MME c.1188+428A>G variant created a novel splice donor site resulting in the inclusion of an 83 bp pseudoexon between MME exons 12 and 13. The incorporation of the pseudoexon into MME transcript is predicted to lead to a coding frameshift and premature termination codon (PTC) in MME exon 14 (p.Ala397ProfsTer47). This PTC is likely to result in nonsense mediated decay (NMD) of MME transcript leading to a pathogenic loss-of-function.

INTERPRETATION:

To our knowledge, this is the first report of a pathogenic deep intronic MME variant causing CMT. This is of significance as deep intronic variants are missed using whole exome sequencing screening methods. Individuals with CMT should be reassessed for deep intronic variants, with splicing impacts being considered in relation to the potential pathogenicity of variants.
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Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Metaloendopeptidasas / Enfermedad de Charcot-Marie-Tooth / Empalme del ARN Límite: Adult / Female / Humans / Male Idioma: En Revista: J Peripher Nerv Syst Asunto de la revista: NEUROLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos
Texto completo
Añadir a Mi BVS
Imprimir
XML
PubMed Links
Buscar en Google

Texto completo: 1 Colección: 01-internacional Base de datos: MEDLINE Asunto principal: Metaloendopeptidasas / Enfermedad de Charcot-Marie-Tooth / Empalme del ARN Límite: Adult / Female / Humans / Male Idioma: En Revista: J Peripher Nerv Syst Asunto de la revista: NEUROLOGIA Año: 2024 Tipo del documento: Article País de afiliación: Australia Pais de publicación: Estados Unidos