Mendoza-Ferreira, Natalia, Coutelier, Marie ORCID: 0000-0002-0261-7210, Janzen, Eva, Hosseinibarkooie, Seyyedmohsen, Loehr, Heiko, Schneider, Svenja, Milbradt, Janine, Karakaya, Mert, Riessland, Markus ORCID: 0000-0003-2592-5045, Pichlo, Christian, Torres-Benito, Laura, Singleton, Andrew, Zuchner, Stephan, Brice, Alexis, Durr, Alexandra, Hammerschmidt, Matthias, Stevanin, Giovanni ORCID: 0000-0001-9368-8657 and Wirth, Brunhilde ORCID: 0000-0003-4051-5191 (2018). Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function. Neurol.-Genet., 4 (1). PHILADELPHIA: LIPPINCOTT WILLIAMS & WILKINS. ISSN 2376-7839

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Abstract

Objective: To ascertain the genetic and functional basis of complex autosomal recessive cerebellar ataxia (ARCA) presented by 2 siblings of a consanguineous family characterized by motor neuropathy, cerebellar atrophy, spastic paraparesis, intellectual disability, and slow ocular saccades. Methods: Combined whole-genome linkage analysis, whole-exome sequencing, and focused screening for identification of potential causative genes were performed. Assessment of the functional consequences of the mutation on protein function via subcellular fractionation, size-exclusion chromatography, and fluorescence microscopy were done. A zebrafish model, using Morpholinos, was generated to study the pathogenic effect of the mutation in vivo. Results: We identified a biallelic 3-bp deletion (p.K19del) in CHP1 that cosegregates with the disease. Neither focused screening for CHP1 variants in 2 cohorts (ARCA: N = 319 and NeurO-mics: N = 657) nor interrogating GeneMatcher yielded additional variants, thus revealing the scarcity of CHP1 mutations. We show that mutant CHP1 fails to integrate into functional protein complexes and is prone to aggregation, thereby leading to diminished levels of soluble CHP1 and reduced membrane targeting of NHE1, a major Na+/H+ exchanger implicated in syndromic ataxia-deafness. Chp1 deficiency in zebrafish, resembling the affected individuals, led to movement defects, cerebellar hypoplasia, and motor axon abnormalities, which were ameliorated by coinjection with wild-type, but not mutant, human CHP1 messenger RNA. Conclusions: Collectively, our results identified CHP1 as a novel ataxia-causative gene in humans, further expanding the spectrum of ARCA-associated loci, and corroborated the crucial role of NHE1 within the pathogenesis of these disorders.

Item Type: Journal Article
Creators:
CreatorsEmailORCIDORCID Put Code
Mendoza-Ferreira, NataliaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Coutelier, MarieUNSPECIFIEDorcid.org/0000-0002-0261-7210UNSPECIFIED
Janzen, EvaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hosseinibarkooie, SeyyedmohsenUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Loehr, HeikoUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Schneider, SvenjaUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Milbradt, JanineUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Karakaya, MertUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Riessland, MarkusUNSPECIFIEDorcid.org/0000-0003-2592-5045UNSPECIFIED
Pichlo, ChristianUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Torres-Benito, LauraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Singleton, AndrewUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Zuchner, StephanUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Brice, AlexisUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Durr, AlexandraUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Hammerschmidt, MatthiasUNSPECIFIEDUNSPECIFIEDUNSPECIFIED
Stevanin, GiovanniUNSPECIFIEDorcid.org/0000-0001-9368-8657UNSPECIFIED
Wirth, BrunhildeUNSPECIFIEDorcid.org/0000-0003-4051-5191UNSPECIFIED
URN: urn:nbn:de:hbz:38-196884
DOI: 10.1212/NXG.0000000000000209
Journal or Publication Title: Neurol.-Genet.
Volume: 4
Number: 1
Date: 2018
Publisher: LIPPINCOTT WILLIAMS & WILKINS
Place of Publication: PHILADELPHIA
ISSN: 2376-7839
Language: English
Faculty: Unspecified
Divisions: Unspecified
Subjects: no entry
Uncontrolled Keywords:
KeywordsLanguage
CALCINEURIN HOMOLOGOUS PROTEIN-1; NA+/H+ EXCHANGER; IN-VIVO; GENE; FORM; DEGENERATION; MICROTUBULES; AGGREGATION; EXPRESSION; MATURATIONMultiple languages
Genetics & Heredity; Clinical NeurologyMultiple languages
Refereed: Yes
URI: http://kups.ub.uni-koeln.de/id/eprint/19688

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