Whole-Exome Sequencing Identifies Homozygous AFG3L2 Mutations in a Spastic Ataxia-Neuropathy Syndrome Linked to Mitochondrial m-AAA Proteases

被引：172

作者：

Pierson, Tyler Mark ^{[1
,3
]}

Adams, David ^{[1
,2
]}

Bonn, Florian

Martinelli, Paola ^{[4
]}

Cherukuri, Praveen F. ^{[5
]}

Teer, Jamie K. ^{[6
]}

Hansen, Nancy F. ^{[5
]}

Cruz, Pedro ^{[5
]}

Mullikin, James C. ^{[5
,7
]}

Blakesley, Robert W. ^{[5
]}

Golas, Gretchen ^{[1
,2
]}

Kwan, Justin ^{[8
]}

Sandler, Anthony ^{[9
]}

Fajardo, Karin Fuentes ^{[1
]}

Markello, Thomas ^{[1
,2
]}

Tifft, Cynthia ^{[1
,2
]}

Blackstone, Craig ^{[3
]}

Rugarli, Elena I. ^{[4
]}

Langer, Thomas ^{[10
,11
]}

Gahl, William A. ^{[1
,2
]}

Toro, Camilo ^{[1
]}

机构：

[1] Natl Inst Hlth Off Rare Dis Res, NIH Undiagnosed Dis Program, Bethesda, MD USA

[2] NHGRI, Off Clin Director, NIH, Bethesda, MD 20892 USA

[3] Natl Inst Neurol Disorders & Stroke, Neurogenet Branch, NIH, Bethesda, MD USA

[4] Univ Cologne, Bioctr, Cologne, Germany

[5] NHGRI, Genome Technol Branch, NIH, Bethesda, MD 20892 USA

[6] NHGRI, Genet Dis Res Branch, NIH, Bethesda, MD 20892 USA

[7] NHGRI, NIH Intramural Sequencing Ctr, NIH, Bethesda, MD 20892 USA

[8] Natl Inst Neurol Disorders & Stroke, EMG Sect, NIH, Bethesda, MD USA

[9] Childrens Natl Med Ctr, Div Surg, Washington, DC 20010 USA

[10] Univ Cologne, Inst Genet, Ctr Mol Med CMMC, Cologne Excellence Cluster Cellular Stress Respon, D-5000 Cologne, Germany

[11] Max Planck Inst Biol Aging, Cologne, Germany

来源：

PLOS GENETICS | 2011年 / 7卷 / 10期

基金：

美国国家卫生研究院; 欧洲研究理事会;

关键词：

DIMETHYLGLYCINE DEHYDROGENASE; INBORN ERROR; PARAPLEGIA; DEGENERATION; SCA28; GENE; METALLOPROTEASE; IMPAIRMENT; DEFICIENCY; METABOLISM;

D O I：

10.1371/journal.pgen.1002325

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

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.

引用

页数：10

共 33 条

[31] m-AAA protease-driven membrane dislocation allows intramembrane cleavage by rhomboid in mitochondria [J].