Missense mutations in the AFG3L2 proteolytic domain account for ∼1.5% of European autosomal dominant cerebellar ataxias.
Hum. Mutat.. 2010-09-07; 31(10): 1117-1124
DOI: 10.1002/humu.21342
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1. Hum Mutat. 2010 Oct;31(10):1117-24. doi: 10.1002/humu.21342.
Missense mutations in the AFG3L2 proteolytic domain account for ∼1.5% of European
autosomal dominant cerebellar ataxias.
Cagnoli C(1), Stevanin G, Brussino A, Barberis M, Mancini C, Margolis RL, Holmes
SE, Nobili M, Forlani S, Padovan S, Pappi P, Zaros C, Leber I, Ribai P, Pugliese
L, Assalto C, Brice A, Migone N, Dürr A, Brusco A.
Author information:
(1)Department of Genetics, Biology and Biochemistry, University of Torino,
Torino, Italy.
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.
Hum Mutat 31:1117-1124, 2010. © 2010 Wiley-Liss, Inc.
DOI: 10.1002/humu.21342
PMID: 20725928 [Indexed for MEDLINE]