KIF1A – Hereditary Sensory and Autonomic Neuropathy Type 2

Hereditary sensory and autonomic neuropathy type 2 (HSAN2) is a rare autosomal recessive disorder marked by severe distal sensory loss and peripheral nerve degeneration. The kinesin family member 1A gene (KIF1A) encodes an axonal motor protein critical for synaptic vesicle transport. Initial evidence identified a truncating homozygous variant in a consanguineous Afghan family, with three additional unrelated families harboring distinct loss-of-function alleles, establishing KIF1A as an HSAN2 gene (PMID:21820098).

Inheritance is autosomal recessive, with four probands confirmed to carry biallelic KIF1A truncating mutations segregating with disease in multiple generations ([PMID:21820098]). Segregation analysis showed perfect co-segregation in affected relatives across these families. Case-level data include four independent probands with homozygous splice-site or frameshift variants. Variant spectrum is dominated by loss-of-function changes (nonsense, frameshift, splice donor) clustering in an alternatively spliced exon critical for motor function, with no recurrent founder alleles reported.

One representative variant, c.200dup (p.Tyr67Ter) (PMID:21820098), disrupts the motor domain and abolishes KIF1A function. No confirmed missense or deep-intronic variants have been reported for HSAN2, consistent with a loss-of-function mechanism. Population databases lack these alleles, supporting their rarity and pathogenicity under recessive inheritance.

Functional studies provided limited but supportive evidence: yeast two-hybrid screening demonstrated direct interaction of KIF1A with the HSN2 exon product, and homozygosity mapping localized the disease locus to KIF1A in affected pedigrees. These data align with a loss-of-function mechanism leading to peripheral sensory neuron degeneration.

No conflicting reports have emerged disputing KIF1A’s role in HSAN2. The combination of multiple unrelated recessive cases, segregation in families, and concordant functional data justifies a Moderate clinical validity classification for the KIF1A–HSAN2 association.

Key Take-Home: KIF1A loss-of-function variants cause autosomal recessive HSAN2, warranting inclusion of KIF1A in diagnostic gene panels for sensory neuropathies and facilitating genetic counseling and carrier testing.

References

• American Journal of Human Genetics • 2011 • KIF1A, an axonal transporter of synaptic vesicles, is mutated in hereditary sensory and autonomic neuropathy type 2. PMID:21820098

Evidence Based Scoring (AI generated)