CHP1 - a novel gene responsible for cerebellar ataxia identified by Whole Exome Sequencing

01/24/2018

A collaborative effort between the research groups of Brunhilde Wirth (Inst. of Human Genetics (Univ. Hospital of Cologne) and the CMMC and Giovanni Stevanin (Neurogenetics Inst., INSERM) succeeded to identify a novel mutation in the gene CHP1 as a novel cause of Cerebellar Ataxia.

The study was recently published in the magazine Neurology Genetics, an official journal of the American Academy of Neurology. 

Autosomal Recessive Cerebellar Ataxias (ARCAs) are a heterogeneous group of complex neurodegenerative conditions associated with atrophy of the cerebellum, the portion of our brain that controls precision, coordination and accurate timing of voluntary muscle movements, like walking, writing and speaking. The genetic cause of these devastating disorders is unknown in at least 40 percent of the patients.

The novel CHP1 mutation was identified by Whole Exome Sequencing (WES) in a family with one healthy child and two children affected with ARCA. Natalia Mendoza Ferreira, PhD student in the Wirth lab, further assessed the functional effect of the mutation on protein function and expression and confirmed that the mutant CHP1 protein is insoluble and therefore prone to aggregate.

With the purpose to analyze the pathogenic consequences of CHP1 reduction in a vertebrate animal model, Natalia Mendoza Ferreira developed a zebrafish model of reduced CHP1 expression using morpholinos that block the translation and synthesis of the protein. Closely resembling the clinical features of the ARCA-affected individuals, CHP1 deficiency in zebrafish led to an ataxia-like phenotype characterized by cerebellar atrophy, motor neuropathy and abnormal “ataxic” contractions.

This work has been carried out as a part of a large EU-funded project (NeurOmics; www.rd-neuromics.eu) to implement Next Generation Sequencing (NGS) technologies to identify novel genes for rare disorders. During the past five years, the entire consortium identified more than 100 novel disease-causing genes for neurodegenerative and neuromuscular disorders.

The study was recently published in the magazine Neurology Genetics, an official journal of the American Academy of Neurology.
Biallelic CHP1 mutation causes human autosomal recessive ataxia by impairing NHE1 function
Natalia Mendoza Ferreira, Marie Coutelier, Eva Janzen, Seyyedmohsen Hosseinibarkooie, Heiko Löhr, Svenja Schneider, Janine Milbradt, Mert Karakaya, Markus Riessland, Christian Pichlo, Laura Torres-Benito, Andrew Singleton, Stephan Zuchner, Alexis Brice, Alexandra Durr, Matthias Hammerschmidt, Giovanni Stevanin, Brunhilde Wirth.
Neurology Genetics®. February, 2018. DOI    10.1212/NXG.0000000000000209

Contact:
Prof. Dr. Brunhilde Wirth
Chair - Institute of Human Genetics
Principal Investigator - Center for Molecular Medicine Cologne
brunhilde.wirth[at]uk-koeln.de