Abstract
Ataxia is a symptom that is often associated with syndromic inherited diseases. We previously reported the linkage of a novel syndrome, ataxia with blindness and deafness (SCAR3/SCABD, OMIM# 271250), to chromosome 6p21–p23 by linkage mapping of an Arab Israeli consanguineous family. We have now identified by whole-exome sequencing a homozygous missense mutation in the Arab Israeli family in the SLC52A2 gene located in 8qter, therefore excluding linkage of this family to 6p. We confirmed the involvement of SLC52A2 by the identification of a second mutation in an independent family with an identical syndromic presentation, which we suggest to name SCABD2. SCABD2 is therefore allelic to Brown–Vialleto–Van Laere syndrome type 2 defined by prominent motoneuronopathy and deafness, and also caused by SLC52A2 mutations. In the course of this project, we identified a clinically similar family with a homozygous missense mutation in PEX6, which is located in 6p21. Therefore, despite false linkage in the initial family, SCABD1/SCAR3 is located in 6p21 and is caused by PEX6 mutations. Both SLC52A2 and PEX6 should be included in screening panels for the diagnosis of syndromic inherited ataxias, particularly as patients with mutations in SLC52A2 can be ameliorated by riboflavin supplementation.
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References
Anheim M, Tranchant C, Koenig M : The autosomal recessive cerebellar ataxias. N Engl J Med 2012; 366: 636–646.
Brown CH : Infantile amyotrophic lateral sclerosis of the family type. J Nerv Ment Dis 1894; 19: 707–716.
Foley AR, Menezes MP, Pandraud A et al: Treatable childhood neuronopathy caused by mutations in riboflavin transporter RFVT2. Brain 2014; 137: 44–56.
Steinberg SJ, Dodt G, Raymond GV, Braverman NE, Moser AB, Moser HW : Peroxisome biogenesis disorders. Biochim Biophys Acta 2006; 1763: 1733–1748.
Nikali K, Suomalainen A, Saharinen J et al: Infantile onset spinocerebellar ataxia is caused by recessive mutations in mitochondrial proteins Twinkle and Twinky. Hum Mol Genet 2005; 14: 2981–2990.
Ben Hamida C, Doerflinger N, Belal S et al: Localization of Friedreich ataxia phenotype with selective vitamin E deficiency to chromosome 8q by homozygosity mapping. Nat Genet 1993; 5: 195–200.
Ouahchi K, Arita M, Kayden H et al: Ataxia with isolated vitamin E deficiency is caused by mutations in the alpha-tocopherol transfer protein. Nat Genet 1995; 9: 141–145.
Moreira MC, Barbot C, Tachi N et al: The gene mutated in ataxia-ocular apraxia 1 encodes the new HIT/Zn-finger protein aprataxin. Nat Genet 2001; 29: 189–193.
Moreira M-C, Klur S, Watanabe M et al: Senataxin, the ortholog of a yeast RNA helicase, is mutant in ataxia-ocular apraxia 2. Nat Genet 2004; 36: 225–227.
Bomont P, Watanabe M, Gershoni-Barush R et al: Homozygosity mapping of spinocerebellar ataxia with cerebellar atrophy and peripheral neuropathy to 9q33-34, and with hearing impairment and optic atrophy to 6p21-23. Eur J Hum Genet 2000; 8: 986–990.
DePristo MA, Banks E, Poplin R et al: A framework for variation discovery and genotyping using next-generation DNA sequencing data. Nat Genet 2011; 43: 491–498.
Geoffroy V, Pizot C, Redin C et al: VaRank: a simple and powerful tool for ranking genetic variants. PeerJ 2015; 3: e796.
Redin C, Le Gras S, Mhamdi O et al: Targeted high-throughput sequencing for diagnosis of genetically heterogeneous diseases: efficient mutation detection in Bardet-Biedl and Alström syndromes. J Med Genet 2012; 49: 502–512.
Lagier-Tourenne C, Tazir M, López LC et al: ADCK3, an ancestral kinase, is mutated in a form of recessive ataxia associated with coenzyme Q10 deficiency. Am J Hum Genet 2008; 82: 661–672.
Haack TB, Makowski C, Yao Y et al: Impaired riboflavin transport due to missense mutations in SLC52A2 causes Brown-Vialetto-Van Laere syndrome. J Inherit Metab Dis 2012; 35: 943–948.
Johnson JO, Gibbs JR, Megarbane A et al: Exome sequencing reveals riboflavin transporter mutations as a cause of motor neuron disease. Brain 2012; 135: 2875–2882.
Klein SL, Neilson KM, Orban J et al: Conserved structural domains in FoxD4L1, a neural forkhead box transcription factor, are required to repress or activate target genes. PLoS One 2013; 8: e61845.
Hall PA, Jung K, Hillan KJ, Russell SEH : Expression profiling the human septin gene family. J Pathol 2005; 206: 269–278.
Chen Z, Kastaniotis AJ, Miinalainen IJ, Rajaram V, Wierenga RK, Hiltunen JK : 17beta-hydroxysteroid dehydrogenase type 8 and carbonyl reductase type 4 assemble as a ketoacyl reductase of human mitochondrial FAS. FASEB J 2009; 23: 3682–3691.
Collins CS, Kalish JE, Morrell JC, McCaffery JM, Gould SJ : The peroxisome biogenesis factors pex4p, pex22p, pex1p, and pex6p act in the terminal steps of peroxisomal matrix protein import. Mol Cell Biol 2000; 20: 7516–7526.
Najmabadi H, Hu H, Garshasbi M et al: Deep sequencing reveals 50 novel genes for recessive cognitive disorders. Nature 2011; 478: 57–63.
Tran C, Hewson S, Steinberg SJ, Mercimek-Mahmutoglu S : Late-onset Zellweger spectrum disorder caused by PEX6 mutations mimicking X-Linked adrenoleukodystrophy. Pediatr Neurol 2014; 51: 262–265.
Acknowledgements
We acknowledge Bernard Jost, Serge Vicaire, Stéphanie Legras, Michael Dumas, Véronique Geoffroy and Jean-Philippe Villemin for next-generation sequencing and analysis. Funding: This study was supported by funds from the Institut National de la Santé et de la Recherche Médicale (INSERM), the Agence Nationale pour la Recherche—Maladies Neurologiques et Psychiatriques (ANR-09-MNPS-001-01 to M.K.), the ANR/E-rare JTC 2011 ‘Euro-SCAR’ (2011-RARE-004-01 to M.K.).
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Guissart, C., Drouot, N., Oncel, I. et al. Genes for spinocerebellar ataxia with blindness and deafness (SCABD/SCAR3, MIM# 271250 and SCABD2). Eur J Hum Genet 24, 1154–1159 (2016). https://doi.org/10.1038/ejhg.2015.259
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DOI: https://doi.org/10.1038/ejhg.2015.259
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