Missense mutations in the AFG3L2 proteolytic domain account for ~1.5% of European autosomal dominant cerebellar ataxias

Claudia Cagnoli, Giovanni Stevanin, Alessandro Brussino, Marco Barberis, Cecilia Mancini, Russell L. Margolis, Susan E. Holmes, Marcello Nobili, Sylvie Forlani, Sergio Padovan, Patrizia Pappi, Cécile Zaros, Isabelle Leber, Pascale Ribai, Luisa Pugliese, Corrado Assalto, Alexis Brice, Nicola Migone, Alexandra Dürr, Alfredo Brusco

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62 Scopus citations


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.

Original languageEnglish (US)
Pages (from-to)1117-1124
Number of pages8
JournalHuman mutation
Issue number10
StatePublished - Oct 2010


  • AFG3L2
  • Autosomal dominant cerebellar ataxia
  • SCA28
  • Spinocerebellar ataxia

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)


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