Biallelic variants in SLC4A10 encoding the sodium-dependent chloride-bicarbonate exchanger NCBE lead to a neurodevelopmental disorder
Abstract: Purpose
SLC4A10 encodes a plasma membrane-bound transporter, which mediates Na+-dependent HCO3− import, thus mediating net acid extrusion. Slc4a10 knockout 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 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 modeling were performed to study the possible functional consequences of the variant alleles.
Results
The families harbor 8 segregating ultra-rare biallelic SLC4A10 variants (7 missense and 1 splicing). Phenotypically, patients present with global developmental delay/intellectual disability and central hypotonia, accompanied by variable speech delay, microcephaly, cerebellar ataxia, facial dysmorphism, and infrequently, epilepsy. 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 of 7 missense variants affect evolutionarily conserved residues. Functional analyses supported the pathogenicity of 4 of 7 missense variants.
Conclusion
We provide evidence that pathogenic biallelic SLC4A10 variants can lead to neurodevelopmental disorders characterized by variable abnormalities of the central nervous system, including altered brain ventricles, thus resembling several features observed in knockout mice
- Standort
-
Deutsche Nationalbibliothek Frankfurt am Main
- Umfang
-
Online-Ressource
- Sprache
-
Englisch
- Anmerkungen
-
Genetics in medicine. - 26, 3 (2024) , 101034, ISSN: 1530-0366
- Ereignis
-
Veröffentlichung
- (wo)
-
Freiburg
- (wer)
-
Universität
- (wann)
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2023
- Urheber
- DOI
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10.1016/j.gim.2023.101034
- URN
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urn:nbn:de:bsz:25-freidok-2419600
- Rechteinformation
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Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.
- Letzte Aktualisierung
-
28.03.2024, 23:05 MEZ
Datenpartner
Deutsche Nationalbibliothek. Bei Fragen zum Objekt wenden Sie sich bitte an den Datenpartner.
Beteiligte
- Maroofian, Reza
- Zamani, Mina
- Kaiyrzhanov, Rauan
- Liebmann, Lutz
- Schmidts, Miriam
- Hübner, Christian
- Universität
Entstanden
- 2023
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