Missense Mutations in the AFG3L2 Proteolytic Domain Account for ∼1.5% of European Autosomal Dominant Cerebellar Ataxias

Hum Mutat. 2010 Oct;31(10):1117-24. doi: 10.1002/humu.21342.

Abstract

Spinocerebellar ataxia type 28 is an autosomal dominant form of cerebellar ataxia (ADCA) caused by mutations in AFG3L2, a gene that encodes a subunit of the mitochondrial m-AAA protease. We screened 366 primarily Caucasian ADCA families, negative for the most common triplet expansions, for point mutations in AFG3L2 using DHPLC. Whole-gene deletions were excluded in 300 of the patients, and duplications were excluded in 129 patients. We found six missense mutations in nine unrelated index cases (9/366, 2.6%): c.1961C>T (p.Thr654Ile) in exon 15, c.1996A>G (p.Met666Val), c.1997T>G (p.Met666Arg), c.1997T>C (p.Met666Thr), c.2011G>A (p.Gly671Arg), and c.2012G>A (p.Gly671Glu) in exon 16. All mutated amino acids were located in the C-terminal proteolytic domain. In available cases, we demonstrated the mutations segregated with the disease. Mutated amino acids are highly conserved, and bioinformatic analysis indicates the substitutions are likely deleterious. This investigation demonstrates that SCA28 accounts for ∼3% of ADCA Caucasian cases negative for triplet expansions and, in extenso, to ∼1.5% of all ADCA. We further confirm both the involvement of AFG3L2 gene in SCA28 and the presence of a mutational hotspot in exons 15-16. Screening for SCA28, is warranted in patients who test negative for more common SCAs and present with a slowly progressive cerebellar ataxia accompanied by oculomotor signs.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATP-Dependent Proteases / chemistry
  • ATP-Dependent Proteases / genetics*
  • ATPases Associated with Diverse Cellular Activities
  • Adolescent
  • Adult
  • Aged
  • Cerebellar Ataxia / epidemiology*
  • Cerebellar Ataxia / ethnology
  • Cerebellar Ataxia / genetics
  • Cerebellar Ataxia / pathology
  • Child
  • Child, Preschool
  • Computational Biology
  • Europe / epidemiology
  • European Continental Ancestry Group
  • Female
  • Genes, Dominant
  • Humans
  • Infant
  • Male
  • Middle Aged
  • Models, Molecular
  • Mutation, Missense*
  • Pedigree
  • Prevalence
  • Spinocerebellar Ataxias / congenital
  • Spinocerebellar Degenerations / epidemiology
  • Spinocerebellar Degenerations / ethnology
  • Spinocerebellar Degenerations / genetics
  • Spinocerebellar Degenerations / pathology
  • Young Adult

Substances

  • ATP-Dependent Proteases
  • AFG3L2 protein, human
  • ATPases Associated with Diverse Cellular Activities

Supplementary concepts

  • Spinocerebellar ataxia 28