A homozygous splicing mutation in ELAC2 suggests phenotypic variability including intellectual disability with minimal c
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RESEARCH
Open Access
A homozygous splicing mutation in ELAC2 suggests phenotypic variability including intellectual disability with minimal cardiac involvement Nadia A. Akawi1,4, Salma Ben-Salem1, Jozef Hertecant1,2, Anne John1, Thachillath Pramathan3, Praseetha Kizhakkedath1, Bassam R. Ali1† and Lihadh Al-Gazali3*†
Abstract Background: The group of ELAC2-related encephalomyopathies is a recent addition to the rapidly growing heterogeneous mitochondrial disorders. Results: We describe a highly inbred consanguineous Pakistani family with multiple affected children in 2 branches exhibiting moderately severe global developmental delay. Using homozygosity mapping, we mapped the phenotype in this family to a single locus on chromosome 17. In addition, whole-exome sequencing identified a homozygous splicing mutation (c.1423 + 2 T > A) in ELAC2 gene that disrupted the canonical donor splice site of intron 15 of all known isoforms. A noticeable reduction in ELAC2 expression was observed in patients compared to controls. In addition, patients exhibited significantly increased levels of 5′ end unprocessed mt-RNAs compared to the control fibroblast cells. Conclusions: The only three previously reported families with defects in ELAC2 gene exhibited infantile hypertrophic cardiomyopathy and complex I deficiency. In contrast, our patients exhibited intellectual disability as the main feature with minimal cardiac involvement. Therefore our findings expand the phenotypic spectrum of ELAC2- associated disorders illustrating clinical heterogeneity of mutations in this gene. In addition, ELAC2 mutations should be considered when evaluating patient with mainly intellectual disability phenotypes. Keywords: ELAC2, Mitochondrial disorder, 5′ end unprocessed mt-RNAs, Splice site mutation, Intellectual disability, Respiratory chain complex I (RCCI) deficiency
Background Mitochondria are the key suppliers of cellular-energy through five protein complexes known as respiratory chain complexes (RCCI, RCCII, RCCIII, RCCIV, RCCV). These complexes catalyze the oxidation of nutrients and the associated energy transduction into ATP via a pathway known as oxidative phosphorylation. Mitochondrial disorders refer to a group of extremely heterogeneous multisystemic clinical presentations. These disorders are also known as mitochondrial encephalomyopathies since * Correspondence: [email protected] † Equal contributors 3 Department of Paediatrics, College of Medicine and Health Sciences, United Arab Emirates University, P.O. Box 17666, Al-Ain, United Arab Emirates Full list of author information is available at the end of the article
they are almost always involving the muscle and the brain, where energy is highly required [1]. Other clinical manifestations such as blindness, deafness, and movement disabilities may also be present in the spectrum of the mitochondrial group of disorders. Mitochondrial encephalomyopathies are mainly caused by mutations that directly affect the maternally inherited mitochondrial DNA (mt-DNA). In addition, a consider
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