title: Missense mutations in the AFG3L2 proteolytic domain account for ∼1.5% of European autosomal dominant cerebellar ataxias.
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.
authors: Department of Genetics, Biology and Biochemistry, University of Torino, Torino, Italy.
authors: Claudia
authors: C
authors: Cagnoli
authors: Giovanni
authors: G
authors: Stevanin
authors: Alessandro
authors: A
authors: Brussino
authors: Marco
authors: M
authors: Barberis
authors: Cecilia
authors: C
authors: Mancini
authors: Russell L
authors: RL
authors: Margolis
authors: Susan E
authors: SE
authors: Holmes
authors: Marcello
authors: M
authors: Nobili
authors: Sylvie
authors: S
authors: Forlani
authors: Sergio
authors: S
authors: Padovan
authors: Patrizia
authors: P
authors: Pappi
authors: Cécile
authors: C
authors: Zaros
authors: Isabelle
authors: I
authors: Leber
authors: Pascale
authors: P
authors: Ribai
authors: Luisa
authors: L
authors: Pugliese
authors: Corrado
authors: C
authors: Assalto
authors: Alexis
authors: A
authors: Brice
authors: Nicola
authors: N
authors: Migone
authors: Alexandra
authors: A
authors: Dürr
authors: Alfredo
authors: A
authors: Brusco
mesh_terms: 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
chemical_list: D049069:ATP-Dependent Proteases; C120699:AFG3L2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities