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Severe Neurodegenerative Disease in Brothers with Homozygous Mutation in POLR1A

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Severe Neurodegenerative Disease in Brothers with Homozygous Mutation in POLR1A European Journal of Human Genetics (2017) 25, 315–323 & 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved 1018-4813/17 www.nature.com/ejhg ARTICLE Severe neurodegenerative disease in brothers with homozygous mutation in POLR1A Bülent Kara1,11,Çiğdem Köroğlu2,11, Karita Peltonen3, Ruchama C Steinberg4, Hülya Maraş Genç1, Maarit Hölttä-Vuori5,6,Ayşe Güven2, Kristiina Kanerva5,6,Tuğba Kotil7, Seyhun Solakoğlu7, You Zhou6,8, Vesa M Olkkonen5,6, Elina Ikonen5,6, Marikki Laiho3,9,10 and Aslıhan Tolun*,2 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.2801C4T (p.(Ser934Leu)) in POLR1A (encoding RPA194, largest subunit of RNA polymerase I) and c.511C4T (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. European Journal of Human Genetics (2017) 25, 315–323; doi:10.1038/ejhg.2016.183; published online 4 January 2017 INTRODUCTION was homozygous for the OSBPL11 variant but did not carry the Three mammalian polymerases, RNA polymerases (Pol) I, II and III, POLR1A variant. The POLR1A defect was verified to be pathogenic by transcribe the major classes of RNAs: the ribosomal, messenger and molecular modelling studies and functional assays. These findings transfer RNAs. Of these, Pol I transcribes the 47S precursor rRNA that constitute the first report showing a leukodystrophy syndrome is processed to the mature 28S, 18S and 5.8S rRNAs. Pol I associated with POLR1A, encoding RPA194, catalytic subunit of transcription is the critical rate-limiting step in ribosome biogenesis. RNA polymerase I. The transcription is compartmentalized to the nucleolus and attunes to the critical needs of protein synthesis during cell growth, division SUBJECTS AND METHODS – and differentiation.1 3 Defects in three subunits of Pol III, namely, Family POLR1C (shared by Pol I), POLR3A and POLR3B, have been The parents were half-first cousins once removed, with two affected sons and associated with recessive hypomyelinating leukodystrophy.4–6 Defects two healthy daughters (Figure 1). The study was conducted in accordance with in Pol I complex subunits POLR1A, POLR1C and POLR1D cause the Declaration of Helsinki and national guidelines. Informed consent was craniofacial anomalies consistent with perturbed ribosome obtained from/for participants in accordance with the regulations of the ğ biogenesis.7,8 Bo aziçi University Institutional Review Board for Research with Human Leukodystrophies are heterogeneous disorders that primarily affect Participants that approved the study protocol. the white matter and are associated with anomalies of glial cells and Genetic analyses myelin sheath.9 They are classified as hypomyelinating and demyeli- Single-nucleotide polymorphism (SNP) genome scan was performed for the nating according to MRI results. The two brothers born to con- siblings, and multipoint LOD scores were calculated assuming autosomal sanguineous Turkish parents we present here have cerebellar ataxia recessive inheritance, initially with full penetrance and later with 70% associated with spasticity, intellectual disability, cerebellar and cerebral penetrance. All loci 4200 kb and yielding LOD scores of 42 were investigated atrophy, and demyelinating leukodystrophy. Candidate loci were for homozygosity possibly identical by descent. In addition, regions of found by linkage analysis, and homozygous variants in POLR1A and homozygosity shared by the brothers only were searched using Homozygosity OSBPL11 were identified by exome sequencing. An unaffected sister Mapper. Exome of brother 1 was sequenced and data were evaluated as 1Division of Child Neurology, Department of Paediatrics, Kocaeli University Medical Faculty, Kocaeli, Turkey; 2Department of Molecular Biology and Genetics, Boğaziçi University, Istanbul, Turkey; 3Center for Drug Research, University of Helsinki, Helsinki, Finland; 4Cellular and Molecular Medicine Program, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 5Faculty of Medicine, Department of Anatomy, University of Helsinki, Helsinki, Finland; 6Minerva Foundation Institute for Medical Research, Helsinki, Finland; 7Department of Histology and Embryology, Istanbul Faculty of Medicine, Istanbul University, Istanbul, Turkey; 8Systems Immunity University Research Institute and Division of Infection and Immunity, School of Medicine, Cardiff University, Cardiff, UK; 9Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD, USA; 10Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA *Correspondence: Professor A Tolun, Department of Molecular Biology and Genetics, KP 301, Boğaziçi University, Bebek, 34342 Istanbul, Turkey. Tel: +90 212 359 6472 (office)/+90 533 433 0377 (GSM); Fax: +90 212 287 2468; E-mail: [email protected] 11These authors contributed equally to this work. Received 13 June 2016; revised 16 November 2016; accepted 22 November 2016; published online 4 January 2017 POLR1A mutation in neurodegeneration BKaraet al 316 Figure 1 The pedigree and cranial MR images. DNA samples subjected to SNP genotyping are indicated by * on the pedigree, and those for variant testing are indicated by +. POLR1A and OSBPL11 variant genotypes are given. MR images of the brothers revealed enlarged ventricles, cortical sulci and subarachnoid spaces indicative of cerebral atrophy, diffuse hyperintense involvement of periventricular white matter extending to subcortical white matter, atrophy of the cerebellar hemispheres and the vermis, and thin corpus callosum. Brother 2 has additionally a subarachnoid cyst in the left posterior fossa. The sisters have normal MRI findings. Parents have normal white matter and very mild cerebral atrophy. (a) Axial T2 weighted. (b) Coronal T2 weighted. (c) Sagittal T1 weighted. described in Supplementary Methods. Hg19 map was used throughout assess possible interactions between RPA194 and RPA135 (A127 in yeast) based the study. on the prediction of interactions described in 4c2m. Cell culture RPA194 homologue structure, domains, and tertiary structure Fibroblast cultures were established from skin biopsies of the father and sons. prediction Control fibroblast cell lines AG08498 and GM0323 were obtained from Coriell S. cerevisiae The full-length human RPA194 (O95602) and A190 (P10964) Institute for Medical Research (Camden, NJ, USA), and F92-99 has been fi sequences were identi ed and divided into three sections, based on their described previously.15 Fibroblast cell cultures were maintained in Eagle’s predicted domain architecture, for submission to tertiary structure predictions. minimum essential medium supplemented with 15% FBS, 2 mML-glutamine, Yeast A190 was used as a control for the accuracy of the tertiary structure 100 IU/ml penicillin and 100 μg/ml streptomycin. prediction programs as compared with the solved structure.10,11 Domain architecture predictions were made via Pfam, PROSITE, SMART and the Immunofluorescence microscopy and image analysis CDD. The residue of interest, Ser934, locates to the middle section of RPA194 Fibroblasts grown on coverslips were fixed in 3.5% PFA, permeabilized with that we will refer to as RPA194_Segment2. The sequences of RPA194_Seg- 0.5% NP-40 and blocked in 3% BSA. The primary antibodies used were ment2 and A190_Segment2 were submitted for tertiary structure prediction via RPA194 (C-1, Santa Cruz Biotechnology, Santa Cruz, CA, USA) and FBL Phyre2.12 All tertiary structure predictions were subjected to evaluation using (ab582, Abcam, Cambridge, MA, USA). Secondary Alexa488 and Alexa594- ProSAweb and Verify3D.13,14 Models were then ranked by these results, and the conjugated anti-mouse and anti-rabbit antibodies were from Invitrogen best model for RPA194_Segment2 was selected for further analysis. Solved (Carlsbad, CA, USA). DNA was stained using DAPI. Images were captured structures of yeast A190 were submitted for model evaluation as control. using Leica DM6000B fluorescence wide-field microscope equipped with PyMOL was used to visualize the best model and the solved structure 4c2m. Hamamatsu Orca-Flash sCMOS camera, 20 × objective (20 × /0.7 HC PL Using PyMOL, the human RPA194_Segment2 was superimposed with the APO CS, Leica, Wetzlar, Germany) and LasX software (Leica). Image analysis solved structures of yeast A190. Ser934 was then mutated
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