Missense mutations in the AFG3L2 proteolytic domain account for ∼1.5% of European autosomal dominant cerebellar ataxias.
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.
Cagnoli
Claudia
C
Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy.
Stevanin
Giovanni
G
Brussino
Alessandro
A
Barberis
Marco
M
Mancini
Cecilia
C
Margolis
Russell L
RL
Holmes
Susan E
SE
Nobili
Marcello
M
Forlani
Sylvie
S
Padovan
Sergio
S
Pappi
Patrizia
P
Zaros
Cécile
C
Leber
Isabelle
I
Ribai
Pascale
P
Pugliese
Luisa
L
Assalto
Corrado
C
Brice
Alexis
A
Migone
Nicola
N
Dürr
Alexandra
A
Brusco
Alfredo
A
D049069:ATP-Dependent Proteases / Q000737:chemistry / Q000235:genetics*; D000074183:ATPases Associated with Diverse Cellular Activities; D000293:Adolescent; D000328:Adult; D000368:Aged; D002524:Cerebellar Ataxia / Q000453:epidemiology* / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D019295:Computational Biology; D005060:Europe / Q000453:epidemiology; D005260:Female; D005799:Genes, Dominant; D006801:Humans; D007223:Infant; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D020125:Mutation, Missense; D010375:Pedigree; D015995:Prevalence; D020754:Spinocerebellar Ataxias / Q000151:congenital; D013132:Spinocerebellar Degenerations / Q000453:epidemiology / Q000208:ethnology / Q000235:genetics / Q000473:pathology; D044465:White People; D055815:Young Adult
D049069:ATP-Dependent Proteases; C120699:AFG3L2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities