Congenital lethal motor neuron disease with a novel defect in ribosome biogenesis.

Abstract:

OBJECTIVE:We describe a novel congenital motor neuron disease with early demise due to respiratory insufficiency with clinical overlap with spinal muscular atrophy with respiratory distress (SMARD) type 1 but lacking a mutation in the IGHMBP2 gene. METHODS:Exome sequencing was used to identify a de novo mutation in the LAS1L gene in the proband. Pathogenicity of the mutation was validated using a zebrafish model by morpholino-mediated knockdown of las1l. RESULTS:We identified a de novo mutation in the X-linked LAS1L gene in the proband (p.S477N). The mutation is in a highly conserved region of the LAS1L gene predicted to be deleterious by bioinformatic analysis. Morpholino-based knockdown of las1l, the orthologous gene in zebrafish, results in early lethality and disruption of muscle and peripheral nerve architecture. Coinjection of wild-type but not mutant human RNA results in partial rescue of the phenotype. CONCLUSION:We report a patient with a SMARD phenotype due to a mutation in LAS1L, a gene important in coordinating processing of the 45S pre-rRNA and maturation of the large 60S ribosomal subunit. Similarly, the IGHMB2 gene associated with SMARD type 1 has been suggested to have an important role in ribosomal biogenesis from its role in processing the 45S pre-rRNA. We propose that disruption of ribosomal maturation may be a common pathogenic mechanism linking SMARD phenotypes caused by both IGHMBP2 and LAS1L.

journal_name

Neurology

journal_title

Neurology

authors

Butterfield RJ,Stevenson TJ,Xing L,Newcomb TM,Nelson B,Zeng W,Li X,Lu HM,Lu H,Farwell Gonzalez KD,Wei JP,Chao EC,Prior TW,Snyder PJ,Bonkowsky JL,Swoboda KJ

doi

10.1212/WNL.0000000000000305

subject

Has Abstract

pub_date

2014-04-15 00:00:00

pages

1322-30

issue

15

eissn

0028-3878

issn

1526-632X

pii

WNL.0000000000000305

journal_volume

82

pub_type

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