UBQLN2 mutation causing heterogeneous X-linked dominant neurodegeneration

Abstract

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.

Figure 1

X-linked dominant neurodegenerative disease in five generations of family 1T. Clinical status is denoted by fill of pedigree symbols: dark, affected; grey, unknown clinical status; clear, unaffected. Inset: Di-deoxy sequence trace of an affected female confirms the UBQLN2 c.1490C>T mutation identified by exome sequencing. Note the C (blue) and T (red) nucleotide residues, derived from the normal and mutant chromosome X UBQLN2 gene that encode respectively, proline and leucine at position 497. The genotype status for all family members is indicated: +/−, heterozygous mutation; +, hemizygous mutation; −, hemizygous normal allele.

Figure 2

Immunopositive ubiquilin-2 inclusions in brain stem and hippocampus from two affected members of family 1T. Ubiquilin-2 positive intracytoplasmic aggregates (arrows) were identified in neurons in the inferior olivary nucleus along with sparse immunopositive neurites (A, individual II-3; B, individual III-3). Hippocampal aggregates of ubiquilin-2 were detected in the molecular layer (left side of section) of the fascia dentata (C, individual II-3; D, individual III-3). Ubiquilin-2 immunohistochemistry was performed with an ubiquilin-2 polyclonal antibody (Sigma Life Sciences) using diamobenzidine and a hematoxylin counterstain, x400 original magnification.