+ Site Statistics
+ Search Articles
+ PDF Full Text Service
How our service works
Request PDF Full Text
+ Follow Us
Follow on Facebook
Follow on Twitter
Follow on LinkedIn
+ Subscribe to Site Feeds
Most Shared
PDF Full Text
+ Translate
+ Recently Requested

Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease

Infantile onset spinocerebellar ataxia caused by compound heterozygosity for Twinkle mutations and modeling of Twinkle mutations causing recessive disease

Cold Spring Harbor Molecular Case Studies 2(4): A001107

Mutations in nuclear genes required for the replication and maintenance of mitochondrial DNA cause progressive multisystemic neuromuscular disorders with overlapping phenotypes. Biallelic mutations in C10orf2, encoding the Twinkle mitochondrial DNA helicase, lead to infantile-onset cerebellar ataxia (IOSCA), as well as milder and more severe phenotypes. We present a 13-year-old girl with ataxia, severe hearing loss, optic atrophy, peripheral neuropathy, and hypergonadotropic hypogonadism. Whole-exome sequencing revealed that the patient is compound heterozygous for previously unreported variants in the C10orf2 gene: a paternally inherited frameshift variant (c.333delT; p.L112Sfs*3) and a maternally inherited missense variant (c.904C>T; p.R302W). The identification of novel C10orf2 mutations extends the spectrum of mutations in the Twinkle helicase causing recessive disease, in particular the intermediate IOSCA phenotype. Structural modeling suggests that the p.R302W mutation and many other recessively inherited Twinkle mutations impact the position or interactions of the linker region, which is critical for the oligomeric ring structure and activity of the helicase. This study emphasizes the utility of whole-exome sequencing for the genetic diagnosis of a complex multisystemic disorder.

Please choose payment method:

(PDF emailed within 0-6 h: $19.90)

Accession: 058105241

Download citation: RISBibTeXText

PMID: 27551684

DOI: 10.1101/mcs.a001107

Related references

Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. Human Molecular Genetics 14(20): 2981-2990, 2005

Novel Autosomal Recessive c10orf2 Mutations Causing Infantile-Onset Spinocerebellar Ataxia. Case Reports in Pediatrics 2012: 303096-303096, 2012

Identification of a novel Twinkle mutation in a family with infantile onset spinocerebellar ataxia by whole exome sequencing. Pediatric Neurology 46(3): 172-177, 2012

Recessive Twinkle mutations in early onset encephalopathy with mtDNA depletion. Brain 130(Pt 11): 3032-3040, 2007

Recessive C10orf2 mutations in a family with infantile-onset spinocerebellar ataxia, sensorimotor polyneuropathy, and myopathy. Neurogenetics 15(3): 171-182, 2015

Recessive twinkle mutations cause severe epileptic encephalopathy. Brain 132(Pt 6): 1553-1562, 2009

Sporadic infantile-onset spinocerebellar ataxia caused by missense mutations of the inositol 1,4,5-triphosphate receptor type 1 gene. Journal of Neurology 262(5): 1278-1284, 2016

Structural basis for adPEO-causing mutations in the mitochondrial TWINKLE helicase. Human Molecular Genetics 2018, 2018

Digenic progressive external ophthalmoplegia in a sporadic patient: recessive mutations in POLG and C10orf2/Twinkle. Human Mutation 22(2): 175-176, 2003

Next-generation sequencing facilitates the diagnosis in a child with twinkle mutations causing cholestatic liver failure. Journal of Pediatric Gastroenterology and Nutrition 54(2): 291-294, 2012

Compound heterozygosity of two novel truncation mutations in RP1 causing autosomal recessive retinitis pigmentosa. Investigative Ophthalmology and Visual Science 51(4): 2236-2242, 2010

Finding twinkle in the eyes of a 71-year-old lady: a case report and review of the genotypic and phenotypic spectrum of TWINKLE-related dominant disease. American Journal of Medical Genetics. Part A 149a(5): 861-867, 2009

Modeling pathogenic mutations of human twinkle in Drosophila suggests an apoptosis role in response to mitochondrial defects. Plos One 7(8): E43954, 2013

Infantile-onset spinocerebellar ataxia and mitochondrial recessive ataxia syndrome are associated with neuronal complex I defect and mtDNA depletion. Human Molecular Genetics 17(23): 3822-3835, 2008

Twinkle, twinkle little star: photoswitchable fluorophores for super-resolution imaging. Febs Letters 588(19): 3603-3612, 2014