Severe neurodegenerative disease in brothers with homozygous mutation in POLR1A

Kara, Bülent, Köroğlu, Çiğdem, Peltonen, Karita, Steinberg, Ruchama C, Maras Genç, Hülya, Hölttä-Vuori, Maarit, Güven, Ayse, Kanerva, Kristiina, Kotil, Tugba, Solakoğlu, Seyhun, Zhou, You ORCID: https://orcid.org/0000-0002-1743-1291, Olkkonen, Vesa M, Ikonen, Elina, Laiho, Marikki and Tolun, Aslihan 2017. Severe neurodegenerative disease in brothers with homozygous mutation in POLR1A. European Journal of Human Genetics 25 (3) , pp. 315-323. 10.1038/ejhg.2016.183

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Abstract

In two brothers born to consanguineous parents, we identified an unusual neurological disease that manifested with ataxia, psychomotor retardation, cerebellar and cerebral atrophy, and leukodystrophy. Via linkage analysis and exome sequencing, we identified homozygous c.2801C>T (p.(Ser934Leu)) in POLR1A (encoding RPA194, largest subunit of RNA polymerase I) and c.511C>T (p.(Arg171Trp)) in OSBPL11 (encoding oxysterol-binding protein-like protein 11). Although in silico analysis, histopathologic evidence and functional verification indicated that both variants were deleterious, segregation with the patient phenotype established that the POLR1A defect underlies the disease, as a clinically unaffected sister also was homozygous for the OSBPL11 variant. Decreased nucleolar RPA194 was observed in the skin fibroblasts of only the affected brothers, whereas intracellular cholesterol accumulation was observed in the skin biopsies of the patients and the sister homozygous for the OSBPL11 variant. Our findings provide the first report showing a complex leukodystrophy associated with POLR1A. Variants in three other RNA polymerase subunits, POLR1C, POLR3A and POLR3B, are known to cause recessive leukodystrophy similar to the disease afflicting the present family but with a later onset. Of those, POLR1C is also implicated in a mandibulofacial dysostosis syndrome without leukodystrophy as POLR1A is. This syndrome is absent in the family we present.

Item Type:	Article
Date Type:	Publication
Status:	Published
Schools:	Medicine Systems Immunity Research Institute (SIURI)
Subjects:	R Medicine > R Medicine (General)
Publisher:	Nature Publishing Group
ISSN:	1018-4813
Date of First Compliant Deposit:	19 January 2017
Date of Acceptance:	22 November 2016
Last Modified:	22 Nov 2024 05:30
URI:	https://orca.cardiff.ac.uk/id/eprint/97582

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