preproenkephalin and Cerebellar-Ataxia

We have recently identified missense mutations in prodynorphin (PDYN), the precursor to dynorphin opioid peptides, as the cause for spinocerebellar ataxia (SCA23) in Dutch ataxia cases. We report a screen of PDYN for mutations in 371 cerebellar ataxia cases, which had a positive family history; most are of French origin. Sequencing revealed three novel putative missense mutations and one heterozygous two-base pair deletion in four independent SCA patients. These variants were absent in 400 matched controls and are located in the highly conserved dynorphin domain. To resolve the pathogenicity of the heterozygous variants, we assessed the peptide production of the mutant PDYN proteins. Two missense mutations raised dynorphin peptide levels, the two-base pair deletion terminated dynorphin synthesis, and one missense mutation did not affect PDYN processing. Given the outcome of our functional analysis, we may have identified at least two novel PDYN mutations in a French and a Moroccan SCA patient. Our data corroborates recent work that also showed that PDYN mutations only account for a small percentage (~0.1 %) of European SCA cases.

Topics: Adolescent; Adult; Age of Onset; Cerebellar Ataxia; Enkephalins; Female; Genetic Linkage; Heterozygote; Humans; Male; Middle Aged; Mutation; Pedigree; Protein Precursors

Sporadic-onset ataxia is common in a tertiary care setting but a significant percentage remains unidentified despite extensive evaluation. Rare genetic ataxias, reported only in specific populations or families, may contribute to a percentage of sporadic ataxia.. Patients with adult-onset sporadic ataxia, who tested negative for common genetic ataxias (SCA1, SCA2, SCA3, SCA6, SCA7, and/or Friedreich ataxia), were evaluated using a stratified screening approach for variants in 7 rare ataxia genes.. We screened patients for published mutations in SYNE1 (n = 80) and TGM6 (n = 118), copy number variations in LMNB1 (n = 40) and SETX (n = 11), sequence variants in SACS (n = 39) and PDYN (n = 119), and the pentanucleotide insertion of spinocerebellar ataxia type 31 (n = 101). Overall, we identified 1 patient with a LMNB1 duplication, 1 patient with a PDYN variant, and 1 compound SACS heterozygote, including a novel variant.. The rare genetic ataxias examined here do not significantly contribute to sporadic cerebellar ataxia in our tertiary care population.

Topics: Adult; Aged; Cerebellar Ataxia; Cytoskeletal Proteins; Databases, Bibliographic; DNA Helicases; Enkephalins; Female; Genetic Predisposition to Disease; Genetic Testing; Heat-Shock Proteins; Humans; Lamin Type B; Magnetic Resonance Imaging; Male; Middle Aged; Multifunctional Enzymes; Mutation; Nerve Tissue Proteins; Nuclear Proteins; Phenotype; Protein Precursors; RNA Helicases; Transglutaminases