Lethal multiple pterygium syndrome: A severe phenotype associated with a novel mutation in the nebulin gene

Abdalla, Ebtesam; Ravenscroft, Gianina; Zayed, L.; Beecroft, Sarah J.; Laing, Nigel G.

doi:10.1016/j.nmd.2017.01.013

Cited by 18 publications

(17 citation statements)

References 24 publications

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“…In addition, variants in RAPSN (MIM: 60159), encoding a postsynaptic protein that connects and stabilizes AChR, DOK7 (MIM: 610285) and recently identified MUSK (MIM: 601296), have been associated with LMPS (Chen, ; Vogt et al, ). Recently a homozygous variant in the NEB gene has been reported (Abdalla et al, ). In contrast, our cases 1 and 2 showed compound heterozygous variants in NEB in association with complete lack of muscle development.…”

Section: Discussionmentioning

confidence: 99%

Arthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathies

Ahmed

Skaria

Safina

et al. 2017

American J of Med Genetics Pt A

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Arthrogryposis multiplex congenita affects approximately 1 in 3,000 individuals of different ethnic backgrounds and displays an equal incidence in males and females. The underlying mechanism for congenital contracture of the joints is decreased fetal movement during intrauterine development. This disorder is associated with over 400 medical conditions and 350 known genes that display considerable variability in phenotypic expression. In this report, four fetal or perinatal autopsy cases of arthrogryposis were studied by gross morphology, microscopic histopathologic examination, and whole genome sequencing of postmortem DNA. Two stillborn sibling fetuses with arthrogryposis, pterygia, and amyoplasia had compound heterozygous pathogenic variants in NEB. A neonate with a histopathologic diagnosis of nemaline myopathy had a heterozygous de novo pathogenic variant in ACTA1. Another stillborn infant with pterygia and arthrogryposis had a heterozygous de novo likely pathogenic variant in BICD2. These cases demonstrate the utility of whole genome sequencing as the principal diagnostic method of lethal forms of skeletal muscle disorders that present with arthrogryposis and muscle amyoplasia/hypoplasia. Molecular diagnosis provides an opportunity for studying patterns of inheritance and for family counseling concerning future pregnancies.

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Section: Discussionmentioning

confidence: 99%

Arthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathies

Ahmed

Skaria

Safina

et al. 2017

American J of Med Genetics Pt A

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“…To date, over 200 NM-causing pathogenic variants have been identified throughout the entire length of NEB [32,44,64,65]. Variants in NEB can also cause disorders described as distal nebulin myopathy [84], distal NM [45], foetal akinesia/lethal multiple pterygium syndrome [1,44] and, in rare cases, core-rod myopathy [71].…”

Section: Introductionmentioning

confidence: 99%

Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb

Laitila

McNamara

Wingate

et al. 2020

acta neuropathol commun

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Nemaline myopathy (NM) caused by mutations in the gene encoding nebulin (NEB) accounts for at least 50% of all NM cases worldwide, representing a significant disease burden. Most NEB-NM patients have autosomal recessive disease due to a compound heterozygous genotype. Of the few murine models developed for NEB-NM, most are Neb knockout models rather than harbouring Neb mutations. Additionally, some models have a very severe phenotype that limits their application for evaluating disease progression and potential therapies. No existing murine models possess compound heterozygous Neb mutations that reflect the genotype and resulting phenotype present in most patients. We aimed to develop a murine model that more closely matched the underlying genetics of NEB-NM, which could assist elucidation of the pathogenetic mechanisms underlying the disease. Here, we have characterised a mouse strain with compound heterozygous Neb mutations; one missense (p.Tyr2303His), affecting a conserved actin-binding site and one nonsense mutation (p.Tyr935*), introducing a premature stop codon early in the protein. Our studies reveal that this compound heterozygous model, Neb Y2303H, Y935X , has striking skeletal muscle pathology including nemaline bodies. In vitro whole muscle and single myofibre physiology studies also demonstrate functional perturbations. However, no reduction in lifespan was noted. Therefore, Neb Y2303H,Y935X mice recapitulate human NEB-NM and are a much needed addition to the NEB-NM mouse model collection. The moderate phenotype also makes this an appropriate model for studying NEB-NM pathogenesis, and could potentially be suitable for testing therapeutic applications.

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“…The vast majority of patients with NEB mutations have been diagnosed with nemaline myopathy. However, NEB mutations have also been identified in patients with distal nebulin myopathy (four families) [25] , distal nemaline myopathy (three families) [6] , core-rod myopathy (one family) [26] , distal core-rod myopathy (one family) [27] and fetal akinesia/lethal multiple pterygium syndrome (four families) [7,28] . Thus, the NEB -caused myopathies characterized to date constitute a clinically, histologically and genetically heterogeneous group of muscle disorders.…”

Section: Introductionmentioning

confidence: 99%

Dominantly inherited distal nemaline/cap myopathy caused by a large deletion in the nebulin gene

Kiiski

Lehtokari

Vihola

et al. 2019

Neuromuscular Disorders

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We report the first family with a dominantly inherited mutation of the nebulin gene ( NEB ). This ∼100 kb in-frame deletion encompasses NEB exons 14-89, causing distal nemaline/cap myopathy in a three-generation family. It is the largest deletion characterized in NEB hitherto. The mutated allele was shown to be expressed at the mRNA level and furthermore, for the first time, a deletion was shown to cause the production of a smaller mutant nebulin protein. Thus, we suggest that this novel mutant nebulin protein has a dominant-negative effect, explaining the first documented dominant inheritance of nebulin-caused myopathy. The index patient, a young man, was more severely affected than his mother and grandmother. His first symptom was foot drop at the age of three, followed by distal muscle atrophy, slight hypomimia, high-arched palate, and weakness of the neck and elbow flexors, hands, tibialis anterior and toe extensors. Muscle biopsies showed myopathic features with type 1 fibre predominance in the index patient and nemaline bodies and cap-like structures in biopsies from his mother and grandmother. The muscle biopsy findings constitute a further example of nemaline bodies and cap-like structures being part of the same spectrum of pathological changes.

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Lethal multiple pterygium syndrome: A severe phenotype associated with a novel mutation in the nebulin gene

Cited by 18 publications

References 24 publications

Arthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathies

Arthrogryposis and pterygia as lethal end manifestations of genetically defined congenital myopathies

Nebulin nemaline myopathy recapitulated in a compound heterozygous mouse model with both a missense and a nonsense mutation in Neb

Dominantly inherited distal nemaline/cap myopathy caused by a large deletion in the nebulin gene

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