ATL1 – Hereditary Spastic Paraplegia

ATL1 encodes the atlastin-1 GTPase implicated in autosomal-dominant hereditary spastic paraplegia (HSP; MONDO:0019064), also known as SPG3A. Disease-causing variants in ATL1 disrupt homotypic ER membrane fusion in corticospinal neurons, leading to early-onset lower limb spasticity and, in some cases, a complex phenotype with axonal neuropathy. Genetic testing for ATL1 is recommended in patients with childhood-onset spastic paraplegia, including those initially diagnosed with cerebral palsy.

Autosomal dominant ATL1 variants have been reported in at least 12 unrelated probands with HSP, including multiple de novo mutations and familial segregation in 5 families, confirming dominant inheritance (12 probands [PMID:17502470]; 5 families [PMID:14695538]). The majority of pathogenic changes are missense substitutions affecting GTPase or assembly domains, with recurrent mutations such as c.1483C>T (p.Arg495Trp) observed across cohorts. Complex forms with peripheral axonal neuropathy and cerebellar involvement expand the phenotypic spectrum beyond pure lower limb spasticity ([PMID:15742100]; [PMID:19768483]).

Functional assays demonstrate that disease-associated ATL1 variants impair GTP-dependent dimer crossover and ER tubulation. Purified atlastin-1 variants (e.g., p.Arg495Trp, p.Thr162Pro) show reduced tubule/vesicle formation from liposomes, while neuronal models of SPG3A recapitulate axon growth defects and dendritic arborization deficits, both of which can be rescued by microtubule-binding agents ([PMID:19573020]; [PMID:23999326]). These data support a dominant-negative mechanism disrupting ER network dynamics in corticospinal motor neurons.

No significant evidence refutes the ATL1–HSP association; however, rare homozygous ATL1 variants have been described, indicating potential autosomal recessive inheritance in exceptional cases ([PMID:26888483]).

In summary, ATL1 has a strong ClinGen evidence classification for autosomal-dominant HSP (SPG3A), backed by consistent segregation across multiple families, functional concordance in ER fusion assays, and relevant neuronal models. Genetic screening of ATL1 is clinically actionable for early diagnosis, recurrence risk counseling, and therapeutic research targeting ER–microtubule interactions.

Key Take-home: ATL1 pathogenic variants reliably cause autosomal-dominant hereditary spastic paraplegia with characteristic lower limb spasticity, justifying routine inclusion of ATL1 in HSP gene panels.

References

• Archives of neurology • 2007 • Hereditary spastic paraplegia 3A associated with axonal neuropathy. PMID:17502470
• Human mutation • 2004 • Novel mutations in the Atlastin gene (SPG3A) in families with autosomal dominant hereditary spastic paraplegia and evidence for late onset forms of HSP linked to the SPG3A locus. PMID:14695538
• Journal of neurochemistry • 2009 • Atlastin-1, the dynamin-like GTPase responsible for spastic paraplegia SPG3A, remodels lipid membranes and may form tubules and vesicles in the endoplasmic reticulum. PMID:19573020
• Neuroscience research • 2013 • Atlastin-1 regulates dendritic morphogenesis in mouse cerebral cortex. PMID:23999326

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