ARL6IP1 – Hereditary Spastic Paraplegia

ARL6IP1 encodes a tetraspan membrane protein localized to the endoplasmic reticulum and is critical for shaping ER architecture and maintaining ER–mitochondrial contacts. Biallelic loss-of-function variants in ARL6IP1 underlie a severe, early-onset form of Hereditary Spastic Paraplegia, marked by progressive lower limb spasticity, neurodevelopmental impairment, and multisystem involvement.

The disorder follows an autosomal recessive inheritance pattern with homozygous truncating variants segregating in affected kindreds. In a Saudi family, two siblings presented with fatal complicated HSP carrying homozygous c.112C>T (p.Arg38Ter) (PMID:31272422). An independent case with congenital insensitivity to pain and spastic paraplegia harbored homozygous c.346C>T (p.Arg116Ter) and a splice variant c.409-2A>G (PMID:28471035).

The variant spectrum comprises truncating alleles predicted to undergo nonsense-mediated decay and splice-site loss, consistent with a loss-of-function mechanism. No recurrent or founder alleles have been reported to date, and all pathogenic variants identified are private to the affected families.

Functional studies in patient-derived tissues demonstrated reduced ARL6IP1 transcript levels suggestive of NMD (PMID:31272422). In vitro silencing of ARL6IP1 impairs neuronal differentiation and mitochondrial homeostasis by disrupting ER–mitochondrial contacts mediated via LC3B and BCl2L13 interactions.

An Arl6ip1 knockout mouse model recapitulates key HSP features, including corticospinal tract demyelination and white-matter neuroinflammation. Importantly, ARL6IP1 gene delivery in this model restores ER–mitochondrial physiology and ameliorates neurodegenerative pathology, demonstrating therapeutic potential (PMID:37934410).

Collectively, genetic and experimental evidence robustly support ARL6IP1 as a causative gene for autosomal recessive hereditary spastic paraplegia. This association informs molecular diagnosis and highlights ARL6IP1 gene therapy as a promising avenue for clinical intervention. Key takeaway: screening for ARL6IP1 truncating variants should be considered in early-onset complicated HSP.

References

• BMC medical genetics • 2019 • Truncating ARL6IP1 variant as the genetic cause of fatal complicated hereditary spastic paraplegia. PMID:31272422
• Clinical genetics • 2018 • ARL6IP1 mutation causes congenital insensitivity to pain, acromutilation and spastic paraplegia. PMID:28471035
• The Journal of experimental medicine • 2024 • ARL6IP1 gene delivery reduces neuroinflammation and neurodegenerative pathology in hereditary spastic paraplegia model. PMID:37934410

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