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Acadian variant of Fanconi syndrome is caused by mitochondrial respiratory chain complex I deficiency due to a non-coding mutation in complex I assembly factor NDUFAF6
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SYSNO ASEP 0470496 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Acadian variant of Fanconi syndrome is caused by mitochondrial respiratory chain complex I deficiency due to a non-coding mutation in complex I assembly factor NDUFAF6 Tvůrce(i) Hartmannová, H. (CZ)
Piherová, L. (CZ)
Tauchmannová, Kateřina (FGU-C) RID, ORCID
Kidd, K. (US)
Acott, P. D. (CA)
Crocker, J. F. S. (CA)
Oussedik, Y. (CA)
Mallet, M. (CA)
Hodaňová, K. (CZ)
Stránecký, V. (CZ)
Přistoupilová, A. (CZ)
Barešová, V. (CZ)
Jedličková, I. (CZ)
Živná, M. (CZ)
Sovová, J. (CZ)
Hůlková, H. (CZ)
Robins, V. (US)
Vrbacký, Marek (FGU-C) RID, ORCID
Pecina, Petr (FGU-C) RID, ORCID
Kaplanová, Vilma (FGU-C) RID, ORCID
Houštěk, Josef (FGU-C) RID, ORCID
Mráček, Tomáš (FGU-C) RID, ORCID
Thibeault, Y. (CA)
Bleyer, A. J. (US)
Kmoch, S. (CZ)Zdroj.dok. Human Molecular Genetics. - : Oxford University Press - ISSN 0964-6906
Roč. 25, č. 18 (2016), s. 4062-4079Poč.str. 18 s. Jazyk dok. eng - angličtina Země vyd. GB - Velká Británie Klíč. slova Acadian variant of Fanconi syndrome ; mitochondrial complex I deficiency ; NDUFAF6 ; C8ORF38 ; non-coding mutation ; alternative splicing variant ; protein isoforms Vědní obor RIV EB - Genetika a molekulární biologie CEP GB14-36804G GA ČR - Grantová agentura ČR LL1204 GA MŠMT - Ministerstvo školství, mládeže a tělovýchovy Institucionální podpora FGU-C - RVO:67985823 UT WOS 000395806000014 EID SCOPUS 85003449967 DOI 10.1093/hmg/ddw245 Anotace The Acadian variant of Fanconi Syndrome refers to a specific condition characterized by generalized proximal tubular dysfunction from birth, slowly progressive chronic kidney disease and pulmonary interstitial fibrosis. This condition occurs only in Acadians, a founder population in Nova Scotia, Canada. The genetic and molecular basis of the disease is of yet unknown. We carried out whole exome and genome sequencing and found that nine affected individuals were homozygous for the ultra-rare non-coding variant chr8:96046914 T > C; rs575462405, whereas 13 healthy siblings were either heterozygotes or lacked the mutant allele. This variant is located in intron 2 of NDUFAF6 (NM_152416.3; c.298-768 T > C), 37 base pairs upstream from an alternative splicing variant in NDUFAF6 chr8:96046951 A > G; rs74395342 (c.298-731 A > G). NDUFAF6 encodes NADH:ubiquinone oxidoreductase complex assembly factor 6, also known as C8ORF38. We found that rs575462405—either alone or in combination with rs74395342—affects splicing and synthesis of NDUFAF6 isoforms. Affected kidney and lung showed specific loss of the mitochondria-located NDUFAF6 isoform and ultrastructural characteristics of mitochondrial dysfunction. Accordingly, affected tissues had defects in mitochondrial respiration and complex I biogenesis that were corrected with NDUFAF6 cDNA transfection. Our results demonstrate that the Acadian variant of Fanconi Syndrome results from mitochondrial respiratory chain complex I deficiency. This information may be used in the diagnosis and prevention of this disease in individuals and families of Acadian descent and broadens the spectrum of the clinical presentation of mitochondrial diseases, respiratory chain defects and defects of complex I specifically. Pracoviště Fyziologický ústav Kontakt Lucie Trajhanová, lucie.trajhanova@fgu.cas.cz, Tel.: 241 062 400 Rok sběru 2017
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