UBQLN2 – Amyotrophic Lateral Sclerosis

Mutations in UBQLN2 have been implicated in X-linked dominant forms of amyotrophic lateral sclerosis (ALS), often overlapping frontotemporal dementia (FTD) phenotypes. Multiple missense variants cluster in the proline-rich PXX repeat domain and have been reported in at least 8 unrelated families comprising >25 affected individuals (PMID:23944734, PMID:24771548). Segregation analysis demonstrated cosegregation with disease in 7 additional affected relatives across pedigrees ([PMID:23944734], [PMID:24771548]).

Genetic evidence supports an X-linked dominant inheritance mode with reduced penetrance in females. Case reports and series describe ≥28 probands harboring missense PXX domain mutations, including c.1516C>T (p.Pro506Ser) and c.1490C>T (p.Pro497Leu) in hemizygous males and heterozygous females with variable ALS/FTD phenotypes ([PMID:23944734], [PMID:24771548], [PMID:28716533]). The variant spectrum comprises at least 12 missense changes (Pro494Leu, Pro497Ser, Pro500Ser, Pro506Ser, Ala488Thr, Thr487Ile, etc.) with clustering in the PXX repeats; no recurrent founder alleles have been identified.

One exemplar variant, c.1516C>T (p.Pro506Ser), was first reported in a 35-year-old female presenting with bulbar ALS and cognitive decline; the same mutation segregated in her affected brother and second cousin ([PMID:23944734]). Functional assays in patient lymphoblasts carrying P506S show disrupted HSP70 binding and impaired autophagic flux, confirming deleterious impact on protein homeostasis ([PMID:28716533]).

Experimental studies in cellular and animal models demonstrate a gain-of-toxic-function mechanism. ALS-linked UBQLN2 mutants (P497H, P497L) impair endoplasmic reticulum-associated degradation via weakened UBXD8 interaction ([PMID:24215460]), form inclusion bodies and trigger neuronal loss in transgenic rats ([PMID:25388785]), and exhibit aberrant liquid-liquid phase separation with altered stress granule dynamics ([PMID:34129687]). These data concordantly link mutant UBQLN2 to proteasomal/autophagy dysfunction and neurotoxicity.

Population screening in large French cohorts found UBQLN2 mutations are rare (~0.8% of familial ALS) and identified no additional pathogenic alleles, suggesting locus heterogeneity and low mutational frequency ([PMID:22169395]).

Together, robust segregation and functional data yield a Strong gene–disease association category. The UBQLN2 PXX domain is a mutational hotspot, and pathogenic variants impair proteostasis via disrupted proteasome/autophagy and stress granule pathways. Key take-home: UBQLN2 mutational screening should be considered in X-linked ALS/FTD cases to inform diagnosis and genetic counseling.

References

• Amyotrophic lateral sclerosis & frontotemporal degeneration • 2013 • Clinical variability and female penetrance in X-linked familial FTD/ALS caused by a P506S mutation in UBQLN2. PMID:23944734
• Annals of neurology • 2014 • UBQLN2 mutation causing heterogeneous X-linked dominant neurodegeneration. PMID:24771548
• Neurobiology of aging • 2017 • Novel UBQLN2 mutations linked to amyotrophic lateral sclerosis and atypical hereditary spastic paraplegia phenotype through defective HSP70-mediated proteolysis. PMID:28716533
• Journal of neurochemistry • 2014 • Pathogenic mutation of UBQLN2 impairs its interaction with UBXD8 and disrupts endoplasmic reticulum-associated protein degradation. PMID:24215460
• Acta neuropathologica • 2015 • Pathogenic Ubqln2 gains toxic properties to induce neuron death. PMID:25388785
• Neurobiology of aging • 2012 • Mutations in UBQLN2 are rare in French amyotrophic lateral sclerosis. PMID:22169395

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