Recurrent mutations in DNAJC5 cause autosomal dominant Kufs disease

Area of Science:

• Genetics
• Neuroscience
• Molecular Biology

Background:

• Kufs disease is an adult-onset neuronal ceroid lipofuscinosis with an unknown molecular basis.
• Autosomal dominant inheritance patterns suggest a single gene defect.

Purpose of the Study:

• To identify the genetic cause of autosomal dominant Kufs disease.
• To correlate genotype with phenotype in affected individuals.

Main Methods:

• Classic linkage analysis and Next Generation Sequencing were employed.
• Genetic mutations in DNAJC5 were identified in three families.
• Clinical manifestations of 20 individuals with DNAJC5 mutations were analyzed.

Main Results:

• p.L116del and p.L115R mutations in the DNAJC5 gene were identified.
• These mutations segregate with Kufs disease in affected families.
• A homogeneous phenotype was observed, including seizures, myoclonus, ataxia, dementia, and premature death, with onset around age 30.

Conclusions:

• DNAJC5 mutations are the molecular basis of autosomal dominant Kufs disease.
• Specific leucine residue mutations (L115, L116) in DNAJC5 are hotspots.
• These findings establish a link between DNAJC5, CSPα, and progressive myoclonus epilepsy.