English (United Kingdom)

https://curated-unify.zendy.io/wp-json/zendy-region/v1/featured_content/oa?rat=en

https://curated-unify.zendy.io/wp-json/zendy-region/v1/highlighted_journal/

Global: Zendy Plus annual

Presents the access of premium content as premium feature

Premium Content

Presents the keyphrase highlighting as premium feature

Keyphrase Highlighting

Presents the summarisation as premium feature

Summarisation

Insights

Presents the pdf analysis as premium feature

PDF Analysis

Presents the zaia usage as premium feature

ZAIA

Global: Zendy Tools annual

Global: Zendy Free Plan

Global: Zendy Tools monthly

Global: Zendy Plus monthly

Background  Dystonia, cerebellar atrophy, and cardiomyopathy constitute a rare association.    Methods  We used homozygosity mapping and whole exome sequencing to determine the mutation, western blot and immunolabelling on cultured fibroblasts to demonstrate the lower expression and the mislocalization of the protein.    Results  We report on a boy born from consanguineous healthy parents, who presented at three years of age with rapidly progressing dystonia, progressive cerebellar atrophy, and dilated cardiomyopathy. We identified regions of homozygosity and performed whole exome sequencing that revealed a homozygous missense mutation in  TOR1AIP1 . The mutation, absent in controls, results in a change of a highly conserved glutamic acid to alanine.  TOR1AIP1  encodes lamina-associated polypeptide 1 (LAP1), a transmembrane protein ubiquitously expressed in the inner nuclear membrane. LAP1 interacts with torsinA, the protein mutated in DYT1-dystonia.  In vitro  studies in fibroblasts of the patient revealed reduced expression of LAP1 and its mislocalization and aggregation in the endoplasmic reticulum as underlying pathogenic mechanisms.    Conclusions and relevance  The pathogenic role of  TOR1AIP1  mutation is supported by a) the involvement of a highly conserved amino acid, b) the absence of the mutation in controls, c) the functional interaction of LAP1 with torsinA, and d) mislocalization of LAP1 in patient cells. Of note, cardiomyopathy has been reported in LAP1-null mice and in patients with the  TOR1AIP1  nonsense mutation. Other cases will help delineate the clinical spectrum of LAP1-related mutations.    Electronic supplementary material  The online version of this article (doi:10.1186/s13023-014-0174-9) contains supplementary material, which is available to authorized users.

Severe dystonia, cerebellar atrophy, and cardiomyopathy likely caused by a missense mutation in TOR1AIP1