Gene of the Month – January: FGF14

A deep intronic GAA repeat expansion in the gene FGF14 causes a form of cerebellar ataxia manifesting in adulthood. In a study published in the New England Journal of Medicine, scientists identified the molecular cause of an autosomal dominantly inherited late-onset cerebellar ataxia (LOCA) by combining various sequencing approaches and bioinformatic tools. LOCAs are a heterogeneous group of neurodegenerative disorders of the cerebellum, which start to develop after 30 years of age and are associated with progressive motor impairments. They are difficult to diagnose by molecular testing, with almost 75% of affected individuals remaining without a molecular diagnosis.

In the current study, initial whole-genome sequencing in six patients identified the candidate pathogenic heterozygous GAA repeat expansion in intron 1 of FGF14. In a next step, the researchers performed cosegregation studies using long-range PCR and long-read sequencing and determined a threshold of at least 250 GAA repeats. Subsequent analyses in independent patient cohorts from Canada, Germany, Australia and India identified a total of 128 LOCA patients carrying this FGF14 GAA repeat expansion. The study also included functional analyses in postmortem cerebellar tissue and motor neurons derived from induced pluripotent stem cells; they confirmed that the intronic GAA repeat expansion in FGF14 leads to a loss of protein function. FGF14 encodes fibroblast growth factor 14. This protein is expressed in the central nervous system, and specifically in cerebellar granule cells and Purkinje neurons, and interacts with voltage-gated sodium channels.

Pellerin D, Danzi MC, Wilke C, …, Brais B. Deep Intronic FGF14 GAA Repeat Expansion in Late-Onset Cerebellar Ataxia. N Engl J Med. 2023 Jan 12;388(2):128-141. doi: 10.1056/NEJMoa2207406. Epub 2022 Dec 14.

Article in PubMed

Gene of the Month – January: FGF14

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