ATL3 and Hereditary Sensory and Autonomic Neuropathy Type 1

Hereditary sensory and autonomic neuropathy type 1 (HSN1) is an autosomal dominant peripheral neuropathy characterized by distal sensory impairment including numbness, paresthesia, and pain. The subtype HSN1F has been linked to variants in the atlastin GTPase 3 (ATL3) gene essential for endoplasmic reticulum (ER) network dynamics.

Two Iranian families were found to carry a novel heterozygous stop-gain ATL3 variant, c.16C>T (p.Arg6Ter), associated with lower limb sensory disturbances and muscle weakness, confirmed by whole-exome and Sanger sequencing (PMID:36856139). Previously, a recurrent missense variant c.575A>G (p.Tyr192Cys) was identified in two families through exome sequencing and cohort screening (115 patients) (PMID:24459106). In aggregate, four unrelated probands across four families (PMID:36856139; PMID:24459106), with at least four additional affected relatives (PMID:36856139; PMID:24459106), establish robust genetic evidence with autosomal dominant segregation.

The variant spectrum in ATL3 includes one truncating and one missense mutation, each heterozygous and absent from population databases. The p.Arg6Ter change predicts loss-of-function, while p.Tyr192Cys exerts a dominant-negative effect by disrupting ER branch-point localization.

Functional studies in patient fibroblasts and transfected cells demonstrate that HSN1-associated ATL3 mutants promote aberrant ER tethering, forming laterally attached tubule bundles, and in vitro show excessive liposome tethering despite preserved GTPase activity but impaired membrane fusion (PMID:29768202). The p.Tyr192Cys protein mislocalizes and disrupts tubular ER architecture, confirming a dominant-negative pathogenic mechanism (PMID:24459106).

Mechanistically, dominant-negative ATL3 variants compromise ER shaping critical for long-term sensory neuron maintenance, leading to somatic sensory dysfunction, pain, paresthesia, and distal sensory deficits.

Overall, the coalescing genetic and experimental evidence meets ClinGen criteria for a Strong gene–disease association, supporting molecular diagnosis and genetic counseling for Hereditary Sensory and Autonomic Neuropathy Type 1. Key take-home: Pathogenic ATL3 variants with dominant-negative effects underlie HSN1F, informing clinical testing and therapeutic strategies.

References

• Unspecified • Unspecified • Novel ATL3 stop variant (p.Arg6Ter) in HSN1F PMID:36856139
• Cell Reports • 2018 • Sensory-Neuropathy-Causing Mutations in ATL3 Cause Aberrant ER Membrane Tethering. PMID:29768202
• Brain • 2014 • Sensory neuropathy with bone destruction due to a mutation in the membrane-shaping atlastin GTPase 3. PMID:24459106

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