TY - JOUR
T1 - Severe neurodegenerative disease in brothers with homozygous mutation in POLR1A
AU - Kara, Bülent
AU - Köroǧlu, Çiǧdem
AU - Peltonen, Karita
AU - Steinberg, Ruchama C.
AU - Maraş Genç, Hülya
AU - Hölttä-Vuori, Maarit
AU - Güven, Ayşe
AU - Kanerva, Kristiina
AU - Kotil, Tuǧba
AU - Solakoǧlu, Seyhun
AU - Zhou, You
AU - Olkkonen, Vesa M.
AU - Ikonen, Elina
AU - Laiho, Marikki
AU - Tolun, Aslihan
N1 - Funding Information:
This work was supported by the Bogazici University Research Fund (Grant 7695 to AT), Academy of Finland (Grants 263841 and 272130 to EI; 285223 to VMO; and 288364 to ML), the Sigrid Juselius Foundation (to VMO and EI., the Magnus Ehrnrooth Foundation (to VMO) and the National Institutes of Health (R01 CA172069 to ML)
Publisher Copyright:
© 2017 Macmillan Publishers Limited, part of Springer Nature. All rights reserved.
PY - 2017/2/1
Y1 - 2017/2/1
N2 - 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.
AB - 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.
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U2 - 10.1038/ejhg.2016.183
DO - 10.1038/ejhg.2016.183
M3 - Article
C2 - 28051070
AN - SCOPUS:85008420113
SN - 1018-4813
VL - 25
SP - 315
EP - 323
JO - European Journal of Human Genetics
JF - European Journal of Human Genetics
IS - 3
ER -