Dataset Information

Biallelic loss of EMC10 leads to mild to severe intellectual disability.

ABSTRACT: The endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is a highly conserved protein responsible for the post-translational insertion of tail-anchored membrane proteins into the endoplasmic reticulum in a defined topology. Two biallelic variants in EMC10 have previously been associated with a neurodevelopmental disorder. Utilizing exome sequencing and international data sharing we have identified 10 affected individuals from six independent families with five new biallelic loss-of-function and one previously reported recurrent EMC10 variants. This report expands the molecular and clinical spectrum of EMC10 deficiency, provides a comprehensive dysmorphological assessment and highlights an overlap between the clinical features of EMC10-and EMC1-related disease.

SUBMITTER: Kaiyrzhanov R

PROVIDER: S-EPMC9268894 | biostudies-literature | 2022 Jul

REPOSITORIES: biostudies-literature

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Biallelic loss of EMC10 leads to mild to severe intellectual disability.

Kaiyrzhanov Rauan R Rocca Clarissa C Suri Mohnish M Gulieva Sughra S Zaki Maha S MS Henig Noa Z NZ Siquier Karine K Guliyeva Ulviyya U Mounir Samir M SM Marom Daphna D Allahverdiyeva Aynur A Megahed Hisham H van Bokhoven Hans H Cantagrel Vincent V Rad Aboulfazl A Pourkeramti Alemeh A Dehghani Boshra B Shao Diane D DD Markus-Bustani Keren K Sofrin-Drucker Efrat E Orenstein Naama N Salayev Kamran K Arrigoni Filippo F Houlden Henry H Maroofian Reza R

Annals of clinical and translational neurology 20220609 7

The endoplasmic reticulum membrane protein complex subunit 10 (EMC10) is a highly conserved protein responsible for the post-translational insertion of tail-anchored membrane proteins into the endoplasmic reticulum in a defined topology. Two biallelic variants in EMC10 have previously been associated with a neurodevelopmental disorder. Utilizing exome sequencing and international data sharing we have identified 10 affected individuals from six independent families with five new biallelic loss-of ...[more]

PMID: 35684946

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Project description:BackgroundCoat protein complex 1 (COPI) is integral in the sorting and retrograde trafficking of proteins and lipids from the Golgi apparatus to the endoplasmic reticulum (ER). In recent years, coat proteins have been implicated in human diseases known collectively as "coatopathies".MethodsWhole exome or genome sequencing of two families with a neuro-developmental syndrome, variable microcephaly and cataracts revealed biallelic variants in COPB1, which encodes the beta-subunit of COPI (β-COP). To investigate Family 1's splice donor site variant, we undertook patient blood RNA studies and CRISPR/Cas9 modelling of this variant in a homologous region of the Xenopus tropicalis genome. To investigate Family 2's missense variant, we studied cellular phenotypes of human retinal epithelium and embryonic kidney cell lines transfected with a COPB1 expression vector into which we had introduced Family 2's mutation.ResultsWe present a new recessive coatopathy typified by severe developmental delay and cataracts and variable microcephaly. A homozygous splice donor site variant in Family 1 results in two aberrant transcripts, one of which causes skipping of exon 8 in COPB1 pre-mRNA, and a 36 amino acid in-frame deletion, resulting in the loss of a motif at a small interaction interface between β-COP and β'-COP. Xenopus tropicalis animals with a homologous mutation, introduced by CRISPR/Cas9 genome editing, recapitulate features of the human syndrome including microcephaly and cataracts. In vitro modelling of the COPB1 c.1651T>G p.Phe551Val variant in Family 2 identifies defective Golgi to ER recycling of this mutant β-COP, with the mutant protein being retarded in the Golgi.ConclusionsThis adds to the growing body of evidence that COPI subunits are essential in brain development and human health and underlines the utility of exome and genome sequencing coupled with Xenopus tropicalis CRISPR/Cas modelling for the identification and characterisation of novel rare disease genes.

Dataset Information

Biallelic loss of EMC10 leads to mild to severe intellectual disability.

Publications

Biallelic loss of EMC10 leads to mild to severe intellectual disability.

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