Abstract
BackgroundSpinocerebellar ataxia type 28 (SCA28) is related to mutations of the ATPase family gene 3-like 2 gene (AFG3L2). To date, 13 private missense mutations have been identified in families of French, Italian, and German ancestry, but overall, the disorder seems to be rare in Europe. Here, we report a kindred of German ancestry with four affected family members presenting with slowly progressive ataxia, mild pyramidal tract signs and slow saccades.MethodsAfter excluding repeat expansions in the genes for SCA1-3, 6-8, 10, 12, and 17, Sanger sequencing of the coding regions of TTBK2 (SCA11), KCNC3 (SCA13), PRKCG (SCA14), FGF14 (SCA27) and AFG3L2 (SCA28) was performed. The 17 coding exons of AFG3L2 with flanking intronic sequences were amplified by PCR and sequenced on both strands.ResultsSequencing detected a novel potential missense mutation (p.Y689N) in the C-terminal proteolytic domain, the mutational hotspot of AFG3L2. The online programme “PolyPhen-2” classifies this amino acid exchange as probably damaging (score 0.990). Similarly to most of the published SCA28 mutations, the novel mutation is located within exon 16. Mutations in exon 16 alter the proteolytic activity of the protease AFG3L2 that is highly expressed in Purkinje cells.ConclusionsGenetic testing should be considered in dominant ataxia with pyramidal tract signs and saccadic slowing.
Highlights
Spinocerebellar ataxia type 28 (SCA28) is related to mutations of the ATPase family gene 3-like 2 gene (AFG3L2)
The spinocerebellar ataxias (SCAs) represent a clinically and genetically heterogeneous group of inherited neurological disorders with overlapping as well as highly variable phenotypes characterised by progressive incoordination, dysarthria and impaired eye movements
Homozygous ATPase family gene 3-like gene (AFG3L2) mutations were identified in a spastic ataxianeuropathy syndrome [8]
Summary
Subjects Clinical data and blood samples were obtained in four affected individuals (mother: patient 1, three of four children: patients 2 to 4, details see Table 1) and one unaffected sibling (57 years at examination, SARA score 0/ 40, personally examined by DT). Genetic analysis After having obtained informed consent, genomic DNA was extracted from peripheral blood leukocytes by standard protocols. Additional Sanger sequencing of the coding regions of TTBK2 (SCA11), KCNC3 (SCA13), PRKCG (SCA14), and FGF14 (SCA27) identified only known polymorphisms and SNPs. For AFG3L2, the 17 coding exons with flanking intronic sequences were amplified by PCR and sequenced on both strands. Authors’ contributions CZ, BM and GG carried out the molecular genetic studies and helped to draft the manuscript. DT and DW performed clinical examinations and helped to draft the manuscript. KB, performed the clinical examinations and drafted the manuscript. All authors read and approved the final manuscript
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