TY - JOUR
T1 - Missense mutations in the AFG3L2 proteolytic domain account for ~1.5% of European autosomal dominant cerebellar ataxias
AU - Cagnoli, Claudia
AU - Stevanin, Giovanni
AU - Brussino, Alessandro
AU - Barberis, Marco
AU - Mancini, Cecilia
AU - Margolis, Russell L.
AU - Holmes, Susan E.
AU - Nobili, Marcello
AU - Forlani, Sylvie
AU - Padovan, Sergio
AU - Pappi, Patrizia
AU - Zaros, Cécile
AU - Leber, Isabelle
AU - Ribai, Pascale
AU - Pugliese, Luisa
AU - Assalto, Corrado
AU - Brice, Alexis
AU - Migone, Nicola
AU - Dürr, Alexandra
AU - Brusco, Alfredo
PY - 2010/10
Y1 - 2010/10
N2 - 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.
AB - 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.
KW - AFG3L2
KW - Autosomal dominant cerebellar ataxia
KW - SCA28
KW - Spinocerebellar ataxia
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U2 - 10.1002/humu.21342
DO - 10.1002/humu.21342
M3 - Article
C2 - 20725928
AN - SCOPUS:78751600248
SN - 1059-7794
VL - 31
SP - 1117
EP - 1124
JO - Human mutation
JF - Human mutation
IS - 10
ER -