WASHC5 – Spastic Paraplegia 8 (SPG8)

Hereditary spastic paraplegia type 8 (SPG8) is an autosomal dominant upper‐motor neuron disorder caused by mutations in the WASHC5 gene, which encodes the strumpellin subunit of the WASH regulatory complex. SPG8 manifests as progressive lower limb spasticity and gait disturbance, sometimes with bladder dysfunction and impaired vibration sense.

Genetic evidence for SPG8 includes nine distinct WASHC5 mutations identified before 2015 ([PMID:26572744]), plus case reports of novel variants in a Japanese patient ([PMID:26967522]), a Polish patient ([PMID:28878906]), a Chinese patient with a nonsense allele ([PMID:29768361]), four Italian probands ([PMID:31814071]), and a splice‐altering variant in a Chinese family ([PMID:38028608])—17 probands in total across at least 15 unrelated families ([PMID:26572744], [PMID:26967522], [PMID:28878906], [PMID:29768361], [PMID:31814071], [PMID:38028608]). Inheritance is unequivocally autosomal dominant, with multiple familial segregations.

The variant spectrum spans missense, nonsense, frameshift, and splicing mutations without evidence of large deletions. A representative allele is c.2152G>A (p.Glu713Lys), which alters a conserved strumpellin residue and co‐segregates with disease in a Japanese pedigree ([PMID:26967522]). No founder or recurrent alleles have been reported.

Functional studies support a pathogenic mechanism beyond simple haploinsufficiency. Expression of N471D strumpellin in Dictyostelium reveals defects in endolysosomal trafficking and a partial loss of WASH complex function ([PMID:30061306]). SPG8‐associated missense mutants fail to rescue caveolin‐1 abundance and integrin‐mediated adhesion in strumpellin‐deficient cells, linking WASHC5 disruption to impaired membrane dynamics ([PMID:31911435]).

In vivo, N471D WASHC5 knock‐in mice show mild motor and cardiac abnormalities with dysregulation of neurodegeneration‐related proteins, whereas heterozygous knockout mice exhibit no SPG8‐like phenotype, arguing against haploinsufficiency and supporting a toxic gain‐of‐function model ([PMID:34312900]; [PMID:26572744]).

Together, the genetic and experimental data provide moderate clinical validity and mechanistic insight into SPG8. WASHC5 sequencing is essential for diagnosis of AD‐HSP, and understanding the gain‐of‐function mechanism may guide future therapeutic strategies.

References

• Orphanet journal of rare diseases • 2015 • The spectrum of KIAA0196 variants, and characterization of a murine knockout: implications for the mutational mechanism in hereditary spastic paraplegia type SPG8. PMID:26572744
• Clinical neurology and neurosurgery • 2016 • Exome sequencing reveals a novel missense mutation in the KIAA0196 gene in a Japanese patient with SPG8. PMID:26967522
• Clinical case reports • 2017 • First patient with hereditary spastic paraplegia type 8 in Poland. PMID:28878906
• Medicine • 2018 • A novel KIAA0196 mutation in a Chinese patient with spastic paraplegia 8: A case report. PMID:29768361
• Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology • 2020 • SPG8 mutations in Italian families: clinical data and literature review. PMID:31814071
• Frontiers in genetics • 2023 • Case report: A novel WASHC5 variant altering mRNA splicing causes spastic paraplegia in a patient. PMID:38028608
• Disease models & mechanisms • 2018 • Expression of N471D strumpellin leads to defects in the endolysosomal system. PMID:30061306
• Science signaling • 2020 • Hereditary spastic paraplegia SPG8 mutations impair CAV1-dependent, integrin-mediated cell adhesion. PMID:31911435
• Neuropathology and applied neurobiology • 2022 • N471D WASH complex subunit strumpellin knock-in mice display mild motor and cardiac abnormalities and BPTF and KLHL11 dysregulation in brain tissue. PMID:34312900

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