Whole-exome sequencing identifies homozygous AFG3L2 mutations in a spastic ataxia-neuropathy syndrome linked to mitochondrial m-AAA proteases.
We report an early onset spastic ataxia-neuropathy syndrome in two brothers of a consanguineous family characterized clinically by lower extremity spasticity, peripheral neuropathy, ptosis, oculomotor apraxia, dystonia, cerebellar atrophy, and progressive myoclonic epilepsy. Whole-exome sequencing identified a homozygous missense mutation (c.1847G>A; p.Y616C) in AFG3L2, encoding a subunit of an m-AAA protease. m-AAA proteases reside in the mitochondrial inner membrane and are responsible for removal of damaged or misfolded proteins and proteolytic activation of essential mitochondrial proteins. AFG3L2 forms either a homo-oligomeric isoenzyme or a hetero-oligomeric complex with paraplegin, a homologous protein mutated in hereditary spastic paraplegia type 7 (SPG7). Heterozygous loss-of-function mutations in AFG3L2 cause autosomal-dominant spinocerebellar ataxia type 28 (SCA28), a disorder whose phenotype is strikingly different from that of our patients. As defined in yeast complementation assays, the AFG3L2(Y616C) gene product is a hypomorphic variant that exhibited oligomerization defects in yeast as well as in patient fibroblasts. Specifically, the formation of AFG3L2(Y616C) complexes was impaired, both with itself and to a greater extent with paraplegin. This produced an early-onset clinical syndrome that combines the severe phenotypes of SPG7 and SCA28, in additional to other "mitochondrial" features such as oculomotor apraxia, extrapyramidal dysfunction, and myoclonic epilepsy. These findings expand the phenotype associated with AFG3L2 mutations and suggest that AFG3L2-related disease should be considered in the differential diagnosis of spastic ataxias.
NIH Undiagnosed Diseases Program, National Institutes of Health Office of Rare Diseases Research and National Human Genome Research Institute, Bethesda, Maryland, United States of America. piersonty@ninds.nih.gov
Tyler Mark
TM
Pierson
David
D
Adams
Florian
F
Bonn
Paola
P
Martinelli
Praveen F
PF
Cherukuri
Jamie K
JK
Teer
Nancy F
NF
Hansen
Pedro
P
Cruz
James C
JC
Mullikin For The Nisc Comparative Sequencing Program
Robert W
RW
Blakesley
Gretchen
G
Golas
Justin
J
Kwan
Anthony
A
Sandler
Karin
K
Fuentes Fajardo
Thomas
T
Markello
Cynthia
C
Tifft
Craig
C
Blackstone
Elena I
EI
Rugarli
Thomas
T
Langer
William A
WA
Gahl
Camilo
C
Toro
D049069:ATP-Dependent Proteases / Q000235:genetics*; D000074183:ATPases Associated with Diverse Cellular Activities; D000293:Adolescent; D000595:Amino Acid Sequence; D000818:Animals; D001921:Brain / Q000002:abnormalities* / Q000473:pathology; D002648:Child; D003937:Diagnosis, Differential; D059472:Exome / Q000235:genetics; D005838:Genotype; D006367:HeLa Cells; D006720:Homozygote; D006801:Humans; D008297:Male; D008666:Metalloendopeptidases / Q000235:genetics* / Q000378:metabolism; D051379:Mice; D008928:Mitochondria / Q000201:enzymology*; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010264:Paraplegia; D017510:Protein Folding; D035781:Siblings; D015419:Spastic Paraplegia, Hereditary / Q000235:genetics* / Q000473:pathology; D020754:Spinocerebellar Ataxias / Q000151:congenital; D013132:Spinocerebellar Degenerations / Q000235:genetics* / Q000473:pathology; D015003:Yeasts / Q000235:genetics
D049069:ATP-Dependent Proteases; C120699:AFG3L2 protein, human; D008666:Metalloendopeptidases; C112889:SPG7 protein, human; C114583:m-AAA proteases; D000074183:ATPases Associated with Diverse Cellular Activities