UBQLN2 mutation causing heterogeneous X-linked dominant neurodegeneration.
We report a 5-generation family with phenotypically diverse neurodegenerative disease including relentlessly progressive choreoathetoid movements, dysarthria, dysphagia, spastic paralysis, and behavioral dementia in descendants of a 67-year-old woman with amyotrophic lateral sclerosis. Disease onset varied with gender, occurring in male children and adult women. Exome sequence analyses revealed a novel mutation (c.1490C>T, p.P497L) in the ubiquilin-2 gene (UBQLN2) with X-linked inheritance in all studied affected individuals. As ubiquilin-2-positive inclusions were identified in brain, we suggest that mutant peptide predisposes to protein misfolding and accumulation. Our findings expand the spectrum of neurodegenerative phenotypes caused by UBQLN2 mutations.
Department of Genetics, Harvard Medical School, Boston, MA.
Akl C
AC
Fahed
Department of Genetics, Harvard Medical School, Boston, MA.|Cardiovascular Division and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA.
Barbara
B
McDonough
Departments of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS.
Cynthia M
CM
Gouvion
Departments of Pathology and Laboratory Medicine, University of Kansas Medical Center, Kansas City, KS.
Kathy L
KL
Newell
Departments of Neurology and Pediatrics, University of Alabama at Birmingham, Birmingham, AL.
Leon S
LS
Dure
Departments of Neurology and Pediatrics, University of Alabama at Birmingham, Birmingham, AL.
Martina
M
Bebin
Department of Genetics, Harvard Medical School, Boston, MA.
Alexander G
AG
Bick
Department of Genetics, Harvard Medical School, Boston, MA.
J G
JG
Seidman
Department of Neurology, School of Medicine & Health Sciences, The George Washington University, Washington, DC.
Donald H
DH
Harter
Department of Genetics, Harvard Medical School, Boston, MA.|Cardiovascular Division and Howard Hughes Medical Institute, Brigham and Women's Hospital, Boston, MA.
Christine E
CE
Seidman
D048868:Adaptor Proteins, Signal Transducing; D000293:Adolescent; D000328:Adult; D000368:Aged; D000071183:Autophagy-Related Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D002675:Child, Preschool; D005260:Female; D005799:Genes, Dominant; D018740:Genetic Heterogeneity; D020271:Heredodegenerative Disorders, Nervous System / Q000175:diagnosis* / Q000235:genetics*; D006801:Humans; D008297:Male; D009154:Mutation / Q000235:genetics*; D010375:Pedigree; D017510:Protein Folding; D014452:Ubiquitins / Q000235:genetics*; D055815:Young Adult
D048868:Adaptor Proteins, Signal Transducing; D000071183:Autophagy-Related Proteins; D018797:Cell Cycle Proteins; C405662:UBQLN2 protein, human; D014452:Ubiquitins