NIPA1 – Hereditary Spastic Paraplegia Type 6

Autosomal dominant mutations in NIPA1 underlie hereditary spastic paraplegia type 6 (SPG6 HSP), characterized by progressive lower-limb spasticity and variable complex features. Initial sequencing of nine SPG6 families identified recurrent nucleotide changes at mutational hotspots c.315C>T and c.316G>A in eight families (PMID:18191948). Subsequent screening in sporadic and familial cohorts confirmed both de novo occurrences and familial segregation of pathogenic NIPA1 variants.

A large case series encompassing over 110 SPG6 cases, of which 25 (23%) exhibited complex phenotypes including epilepsy, peripheral neuropathy, and cognitive impairment, highlights the allelic and phenotypic spectrum of NIPA1-related disease (PMID:34863451). In a Taiwanese HSP cohort, two heterozygous variants c.316G>A and c.316G>C (both encoding p.Gly106Arg) were found in 0.8% of patients, with one variant associated with complex HSP and reduced protein expression (PMID:36607129). A Chinese series further identified de novo c.126C>G (p.Asn42Lys) in sporadic SPG6, expanding the mutational spectrum and underscoring the need to consider NIPA1 in sporadic AD-HSP (PMID:35464835).

Cosegregation of NIPA1 missense substitutions c.316G>A and c.316G>C with disease in multiple families and de novo in sporadic cases confirms robust genetic evidence. Functional assays demonstrate a gain-of-function mechanism: structural prediction of p.Gly106Arg shows disruption of the third transmembrane domain (PMID:15643603), while in vitro and in vivo models expressing HSP-associated NIPA1 mutants trigger ER stress, unfolded protein response, and progressive neural degeneration in C. elegans (PMID:19091982).

Occasional negative screening in unselected HSP cohorts suggests locus heterogeneity but does not conflict with the established role of NIPA1 in SPG6 (PMID:18191948).

Integration of genetic and experimental data supports a definitive association between NIPA1 and SPG6 HSP, with autosomal dominant inheritance, recurrent mutational hotspots, and gain-of-function pathogenesis. NIPA1 testing is recommended for diagnostic panels in patients with pure and complex hereditary spastic paraplegia.

Key Take-home: NIPA1 variants cause autosomal dominant SPG6 via gain-of-function ER toxicity, supporting inclusion in HSP diagnostic workflows.

References

• Journal of the Neurological Sciences • 2008 • Screening of hereditary spastic paraplegia patients for alterations at NIPA1 mutational hotspots. PMID:18191948
• Human Mutation • 2005 • Distinct novel mutations affecting the same base in the NIPA1 gene cause autosomal dominant hereditary spastic paraplegia in two Chinese families. PMID:15643603
• The Journal of Neuroscience • 2008 • Hereditary spastic paraplegia-associated mutations in the NIPA1 gene and its Caenorhabditis elegans homolog trigger neural degeneration in vitro and in vivo through a gain-of-function mechanism. PMID:19091982
• Journal of Clinical Neuroscience • 2021 • SPG6 (NIPA1 variant): A report of a case with early-onset complex hereditary spastic paraplegia and brief literature review. PMID:34863451
• Frontiers in Genetics • 2022 • Clinical and Genetic Features of Chinese Patients With NIPA1-Related Hereditary Spastic Paraplegia Type 6. PMID:35464835
• Annals of Clinical and Translational Neurology • 2023 • Clinical and genetic characterization of NIPA1 mutations in a Taiwanese cohort with hereditary spastic paraplegia. PMID:36607129

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