ATL1 – Hereditary Sensory and Autonomic Neuropathy Type I

Hereditary sensory and autonomic neuropathy type I (MONDO:0018213) is an autosomal dominant axonal neuropathy marked by prominent sensory loss leading to painless injuries and secondary complications such as osteomyelitis (HP:0002754). The gene ATL1 encodes the large dynamin-related GTPase atlastin-1, previously implicated in SPG3A spastic paraplegia and now linked to sensory neuron maintenance in HSN I.

In the index pedigree, targeted high-throughput sequencing of a 14.3 Mb interval on chromosome 14q identified the heterozygous missense variant c.1065C>A (p.Asn355Lys) segregating with disease in one family (PMID:21194679). This variant was absent from unaffected relatives and public controls, supporting Mendelian co-segregation.

In an expanded cohort of 115 additional HSN I patients (PMID:21194679), two further heterozygous ATL1 variants were discovered: c.196G>C (p.Glu66Gln) and c.976del (p.Val326TrpfsTer8), each in unrelated individuals. These findings total 3 unrelated probands (PMID:21194679), comprising 2 missense substitutions and 1 frameshift truncation.

The variant spectrum includes two amino acid substitutions within the GTPase domain and one protein-truncating deletion. No recurrent or founder mutations were observed, and all alleles arose de novo or in sporadic cases without population clustering.

Functional studies in COS7 cells demonstrated that p.Asn355Lys atlastin-1 exhibits reduced GTP hydrolysis and prominently disrupted endoplasmic reticulum network morphology, consistent with a loss of GTPase-mediated ER fusion function (PMID:21194679). These cell-based assays provide direct mechanistic evidence concordant with the human sensory neuropathy phenotype.

Collectively, three probands across one multiplex family and two sporadic cases with segregation data, combined with concordant functional assays, support a Moderate clinical validity for ATL1 in HSN I. The underlying mechanism likely involves a dominant-negative impairment of atlastin-1 GTPase activity and ER dynamics. Key Take-home: ATL1 mutation screening should be considered in autosomal dominant HSN I for precise molecular diagnosis and informed management.

References

• American journal of human genetics • 2011 • Targeted high-throughput sequencing identifies mutations in atlastin-1 as a cause of hereditary sensory neuropathy type I. PMID:21194679

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