title: Severe neurodegenerative disease in brothers with homozygous mutation in POLR1A.
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.
authors.affiliation: Division of Child Neurology, Department of Paediatrics, Kocaeli University Medical Faculty, Kocaeli, Turkey.
authors.forename: Bülent
authors.initials: B
authors.lastname: Kara
authors.affiliation: Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey.
authors.forename: Çiğdem
authors.initials: Ç
authors.lastname: Köroğlu
authors.affiliation: Center for Drug Research, University of Helsinki, Helsinki, Finland.
authors.forename: Karita
authors.initials: K
authors.lastname: Peltonen
authors.affiliation: Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Ruchama C
authors.initials: RC
authors.lastname: Steinberg
authors.affiliation: Division of Child Neurology, Department of Paediatrics, Kocaeli University Medical Faculty, Kocaeli, Turkey.
authors.forename: Hülya
authors.initials: H
authors.lastname: Maraş Genç
authors.affiliation: Faculty of Medicine, Department of Anatomy, University of Helsinki, Helsinki, Finland.|Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Maarit
authors.initials: M
authors.lastname: Hölttä-Vuori
authors.affiliation: Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey.
authors.forename: Ayşe
authors.initials: A
authors.lastname: Güven
authors.affiliation: Faculty of Medicine, Department of Anatomy, University of Helsinki, Helsinki, Finland.|Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Kristiina
authors.initials: K
authors.lastname: Kanerva
authors.affiliation: Department of Histology and Embryology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Tuğba
authors.initials: T
authors.lastname: Kotil
authors.affiliation: Department of Histology and Embryology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey.
authors.forename: Seyhun
authors.initials: S
authors.lastname: Solakoğlu
authors.affiliation: Minerva Foundation Institute for Medical Research, Helsinki, Finland.|Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK.
authors.forename: You
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Faculty of Medicine, Department of Anatomy, University of Helsinki, Helsinki, Finland.|Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Vesa M
authors.initials: VM
authors.lastname: Olkkonen
authors.affiliation: Faculty of Medicine, Department of Anatomy, University of Helsinki, Helsinki, Finland.|Minerva Foundation Institute for Medical Research, Helsinki, Finland.
authors.forename: Elina
authors.initials: E
authors.lastname: Ikonen
authors.affiliation: Center for Drug Research, University of Helsinki, Helsinki, Finland.|Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA.|Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
authors.forename: Marikki
authors.initials: M
authors.lastname: Laiho
authors.affiliation: Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey.
authors.forename: Aslıhan
authors.initials: A
authors.lastname: Tolun
mesh_terms: D000328:Adult; D001259:Ataxia / Q000175:diagnosis / Q000235:genetics*; D002478:Cells, Cultured; D002648:Child; D002784:Cholesterol / Q000378:metabolism; D012321:DNA-Directed RNA Polymerases / Q000235:genetics* / Q000378:metabolism; D002658:Developmental Disabilities / Q000175:diagnosis / Q000235:genetics*; D005260:Female; D005347:Fibroblasts / Q000378:metabolism; D006720:Homozygote; D006801:Humans; D056784:Leukoencephalopathies / Q000175:diagnosis / Q000235:genetics*; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D011987:Receptors, Steroid / Q000235:genetics / Q000378:metabolism; D035781:Siblings; D013577:Syndrome; D000098825:Oxysterol Binding Proteins
chemical_list: D011987:Receptors, Steroid; D000098825:Oxysterol Binding Proteins; D002784:Cholesterol; D012321:DNA-Directed RNA Polymerases