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- Kariminejad, A., et al.
(författare)
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TOR1A variants cause a severe arthrogryposis with developmental delay, strabismus and tremor
- 2017
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Ingår i: Brain. - : Oxford University Press (OUP). - 0006-8950 .- 1460-2156. ; 140:11, s. 2851-2859
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Tidskriftsartikel (refereegranskat)abstract
- Autosomal dominant torsion dystonia-1 is a disease with incomplete penetrance most often caused by an in-frame GAG deletion (p.Glu303del) in the endoplasmic reticulum luminal protein torsinA encoded by TOR1A. We report an association of the homozygous dominant disease-causing TOR1A p.Glu303del mutation, and a novel homozygous missense variant (p.Gly318Ser) with a severe arthrogryposis phenotype with developmental delay, strabismus and tremor in three unrelated Iranian families. All parents who were carriers of the TOR1A variant showed no evidence of neurological symptoms or signs, indicating decreased penetrance similar to families with autosomal dominant torsion dystonia-1. The results from cell assays demonstrate that the p.Gly318Ser substitution causes a redistribution of torsinA from the endoplasmic reticulum to the nuclear envelope, similar to the hallmark of the p.Glu303del mutation. Our study highlights that TOR1A mutations should be considered in patients with severe arthrogryposis and further expands the phenotypic spectrum associated with TOR1A mutations.
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| 2. |
- Osborn, D. P. S., et al.
(författare)
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Autosomal recessive cardiomyopathy and sudden cardiac death associated with variants in MYL3
- 2021
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Ingår i: Genetics in Medicine. - : Elsevier BV. - 1098-3600 .- 1530-0366. ; 23:4, s. 787-792
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Tidskriftsartikel (refereegranskat)abstract
- Purpose Variants in genes encoding sarcomeric proteins are the most common cause of inherited cardiomyopathies. However, the underlying genetic cause remains unknown in many cases. We used exome sequencing to reveal the genetic etiology in patients with recessive familial cardiomyopathy. Methods Exome sequencing was carried out in three consanguineous families. Functional assessment of the variants was performed. Results Affected individuals presented with hypertrophic or dilated cardiomyopathy of variable severity from infantile- to early adulthood-onset and sudden cardiac death. We identified a homozygous missense substitution (c.170C>A, p.[Ala57Asp]), a homozygous translation stop codon variant (c.106G>T, p.[Glu36Ter]), and a presumable homozygous essential splice acceptor variant (c.482-1G>A, predicted to result in skipping of exon 5). Morpholino knockdown of the MYL3 orthologue in zebrafish, cmlc1, resulted in compromised cardiac function, which could not be rescued by reintroduction of MYL3 carrying either the nonsense c.106G>T or the missense c.170C>A variants. Minigene assay of the c.482-1G>A variant indicated a splicing defect likely resulting in disruption of the EF-hand Ca2+ binding domains. Conclusions Our data demonstrate that homozygous MYL3 loss-of-function variants can cause of recessive cardiomyopathy and occurrence of sudden cardiac death, most likely due to impaired or loss of myosin essential light chain function.
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| 3. |
- Sedghi, M., et al.
(författare)
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Ataxia-telangiectasia-like disorder in a family deficient for MRE11A, caused by a MRE11 variant
- 2018
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Ingår i: Neurology-Genetics. - : Ovid Technologies (Wolters Kluwer Health). - 2376-7839. ; 4:6
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Tidskriftsartikel (refereegranskat)abstract
- Objective We report 3 siblings with the characteristic features of ataxia-telangiectasia-like disorder associated with a homozygous MREll synonymous variant causing nonsense-mediated mRNA decay (NMD) and MRE11A deficiency. Clinical assessments, next-generation sequencing, transcript and immunohistochemistry analyses were performed. The patients presented with poor balance, developmental delay during the first year of age, and suffered from intellectual disability from early childhood. They showed oculomotor apraxia, slurred and explosive speech, limb and gait ataxia, exaggerated deep tendon reflex, dystonic posture, and mirror movement in their hands. They developed mild cognitive abilities. Brain MRI in the index case revealed cerebellar atrophy. Next-generation sequencing revealed a homozygous synonymous variant in MRE11 (c.657C>T, p.Asn219=) that we show affects splicing. A complete absence of MREll transcripts in the index case suggested NMD and immunohistochemistry confirmed the absence of a stable protein. Despite the critical role of MRE11A in double-strand break repair and its contribution to the Mre11/Rad50/Nbs1 complex, the absence of MRE11A is compatible with life.
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