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Maroofian, R.* ; Zamani, M.* ; Kaiyrzhanov, R.* ; Liebmann, L.* ; Ghayoor Karimiani, E.* ; Vona, B.* ; Huebner, A.K.* ; Calame, D.G.* ; Misra, V.K.* ; Sadeghian, S.* ; Azizimalamiri, R.* ; Mohammadi, M.H.* ; Zeighami, J.* ; Heydaran, S.* ; Beiraghi Toosi, M.* ; Akhondian, J.* ; Babaei, M.* ; Hashemi, N.* ; Schnur, R.E.* ; Suri, M.* ; Setzke, J.* ; Wagner, M. ; Brunet, T. ; Grochowski, C.M.* ; Emrick, L.* ; Chung, W.K.* ; Hellmich, U.A.* ; Schmidts, M.* ; Lupski, J.R.* ; Galehdari, H.* ; Severino, M.* ; Houlden, H.* ; Hübner, C.A.*

Biallelic variants in SLC4A10 encoding the sodium-dependent chloride-bicarbonate exchanger NCBE lead to a neurodevelopmental disorder.

Genet. Med. 26:101034 (2023)
Verlagsversion Postprint DOI PMC
Open Access Hybrid
Creative Commons Lizenzvertrag
PURPOSE: SLC4A10 encodes a plasma membrane-bound transporter, which mediates Na+-dependent HCO3- import thus mediating net acid extrusion. Slc4a10 knockout (KO) mice show collapsed brain ventricles, an increased seizure threshold, mild behavioral abnormalities, impaired vision, and deafness. METHODS: Utilizing exome/genome sequencing in families with undiagnosed neurodevelopmental disorders (NDD) and international data sharing, 11 patients from 6 independent families with biallelic variants in SLC4A10 were identified. Clinico-radiological and dysmorphology assessments were conducted. A minigene assay, localization studies, intracellular pH recordings, and protein modelling were performed to study the possible functional consequences of the variant alleles. RESULTS: The families harbour 8 segregating ultra-rare biallelic SLC4A10 variants (7 missense and 1 splicing). Patients phenotypically exhibit global developmental delay/intellectual disability and central hypotonia associated with variable speech delay, microcephaly, cerebellar ataxia, epilepsy, and facial dysmorphism. Neuroimaging features range from some non-specific to distinct neuroradiological findings, including slit ventricles and a peculiar form of bilateral curvilinear nodular heterotopia. In-silico analyses showed 6/7 missense variants affect evolutionarily conserved residues. Functional analyses supported the pathogenicity of 4/7 missense variants. CONCLUSION: We provide evidence that pathogenic biallelic SLC4A10 variants can lead to NDD characterized by variable abnormalities of the central nervous system including altered brain ventricles thus resembling several features observed in KO mice.
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Publikationstyp Artikel: Journalartikel
Dokumenttyp Wissenschaftlicher Artikel
Schlagwörter Neurodevelopmental Disorders ; Slc4a10 ; Bicarbonate Transporters ; Intracellular Ph Dynamics ; Slit Ventricles; Gene-product; Slc4a10; Exchanger; Hco3; Disruption; Membrane; Family; Roles
Sprache englisch
Veröffentlichungsjahr 2023
HGF-Berichtsjahr 2023
ISSN (print) / ISBN 1530-0366
e-ISSN 1098-3600
Zeitschrift Genetics in Medicine
Quellenangaben Band: 26, Heft: 3, Seiten: , Artikelnummer: 101034 Supplement: ,
Verlag Lippincott Williams & Wilkins
Verlagsort Baltimore, Md.
Begutachtungsstatus Peer reviewed
Institut(e) Institute of Neurogenomics (ING)
POF Topic(s) 30205 - Bioengineering and Digital Health
Forschungsfeld(er) Genetics and Epidemiology
PSP-Element(e) G-503200-001
G-503292-001
Förderungen
Alzheimer's Research UK (ARUK)
Sparks GOSH Charity
Rosetrees Trust, Ataxia UK
BBSRC, The Fidelity Trust
National Institute for Health Research University College London Hospitals Biomedical Research Centre
MSA Trust
MRC
Wellcome Trust
CureDRPLA
German Research Foundation (DFG)
Deutsche Forschungsgemeinschaft (DFG)
European Research Council (ERC)
United States National Institutes of Health
Deutsche Forschungsgemeinschaft (DFG, German Research Founda-tion)
NIHR University College London Hospitals Biomedical Research Centre
DOI 10.1016/j.gim.2023.101034
WOS ID 001180051200001
Scopus ID 85185191034
PubMed ID 38054405
Erfassungsdatum 2023-12-20
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