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Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly.

ABSTRACT: The Kennedy pathways catalyse the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus because four of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A) and spastic paraplegia (PCYT2, SELENOI). We identified six individuals from five families with bi-allelic variants in CHKA presenting with severe global developmental delay, epilepsy, movement disorders and microcephaly. Using structural molecular modelling and functional testing of the variants in a cell-based Saccharomyces cerevisiae model, we determined that these variants reduce the enzymatic activity of CHKA and confer a significant impairment of the first enzymatic step of the Kennedy pathway. In summary, we present CHKA as a novel autosomal recessive gene for a neurodevelopmental disorder with epilepsy and microcephaly.

SUBMITTER: Klockner C

PROVIDER: S-EPMC9630884 | biostudies-literature | 2022 Jun

REPOSITORIES: biostudies-literature

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Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly.

Klöckner Chiara C Fernández-Murray J Pedro JP Tavasoli Mahtab M Sticht Heinrich H Stoltenburg-Didinger Gisela G Scholle Leila Motlagh LM Bakhtiari Somayeh S Kruer Michael C MC Darvish Hossein H Firouzabadi Saghar Ghasemi SG Pagnozzi Alex A Shukla Anju A Girisha Katta Mohan KM Narayanan Dhanya Lakshmi DL Kaur Parneet P Maroofian Reza R Zaki Maha S MS Noureldeen Mahmoud M MM Merkenschlager Andreas A Gburek-Augustat Janina J Cali Elisa E Banu Selina S Nahar Kamrun K Efthymiou Stephanie S Houlden Henry H Jamra Rami Abou RA Williams Jason J McMaster Christopher R CR Platzer Konrad K

Brain : a journal of neurology 20220601 6

The Kennedy pathways catalyse the de novo synthesis of phosphatidylcholine and phosphatidylethanolamine, the most abundant components of eukaryotic cell membranes. In recent years, these pathways have moved into clinical focus because four of ten genes involved have been associated with a range of autosomal recessive rare diseases such as a neurodevelopmental disorder with muscular dystrophy (CHKB), bone abnormalities and cone-rod dystrophy (PCYT1A) and spastic paraplegia (PCYT2, SELENOI). We id ...[more]

PMID: 35202461

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Project description:The 2-oxoglutarate dehydrogenase-like (OGDHL) protein is a rate-limiting enzyme in the Krebs cycle that plays a pivotal role in mitochondrial metabolism. OGDHL expression is restricted mainly to the brain in humans. Here, we report nine individuals from eight unrelated families carrying bi-allelic variants in OGDHL with a range of neurological and neurodevelopmental phenotypes including epilepsy, hearing loss, visual impairment, gait ataxia, microcephaly, and hypoplastic corpus callosum. The variants include three homozygous missense variants (p.Pro852Ala, p.Arg244Trp, and p.Arg299Gly), three compound heterozygous single-nucleotide variants (p.Arg673Gln/p.Val488Val, p.Phe734Ser/p.Ala327Val, and p.Trp220Cys/p.Asp491Val), one homozygous frameshift variant (p.Cys553Leufs∗16), and one homozygous stop-gain variant (p.Arg440Ter). To support the pathogenicity of the variants, we developed a novel CRISPR-Cas9-mediated tissue-specific knockout with cDNA rescue system for dOgdh, the Drosophila ortholog of human OGDHL. Pan-neuronal knockout of dOgdh led to developmental lethality as well as defects in Krebs cycle metabolism, which was fully rescued by expression of wild-type dOgdh. Studies using the Drosophila system indicate that p.Arg673Gln, p.Phe734Ser, and p.Arg299Gly are severe loss-of-function alleles, leading to developmental lethality, whereas p.Pro852Ala, p.Ala327Val, p.Trp220Cys, p.Asp491Val, and p.Arg244Trp are hypomorphic alleles, causing behavioral defects. Transcript analysis from fibroblasts obtained from the individual carrying the synonymous variant (c.1464T>C [p.Val488Val]) in family 2 showed that the synonymous variant affects splicing of exon 11 in OGDHL. Human neuronal cells with OGDHL knockout exhibited defects in mitochondrial respiration, indicating the essential role of OGDHL in mitochondrial metabolism in humans. Together, our data establish that the bi-allelic variants in OGDHL are pathogenic, leading to a Mendelian neurodevelopmental disease in humans.

Dataset Information

Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly.

Publications

Bi-allelic variants in CHKA cause a neurodevelopmental disorder with epilepsy and microcephaly.

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