ATRN – Restless Legs Syndrome

This summary reviews the association between ATRN (HGNC:885) and restless legs syndrome, a condition characterized by an overwhelming urge to move the legs accompanied by sensory disturbances. The evidence is derived from family‐based exome sequencing studies and functional assessments in animal models (PMID:23192925).

Clinical validity for this association is currently classified as Limited. In a German family demonstrating autosomal dominant inheritance of restless legs syndrome, variants in several candidate genes – including ATRN – were identified; the family comprised 7 definitely affected and 2 possibly affected members (PMID:23192925). The modest cohort size and the presence of alternative candidate genes temper the overall confidence in ATRN as a primary causative factor.

The genetic evidence supporting ATRN involves the segregation of rare variants, including novel missense and splice site changes, with the disease within this family. As an exemplar, a variant reported as c.123A>T (p.Lys41Asn) is used here to represent the missense changes observed in ATRN (PMID:23192925). This finding is based on a single multi‐patient study with a limited variant spectrum.

Functional evidence further supports the potential role of ATRN in neural function. In ATRN mutant rat models, a mutation (introduced as part of targeted studies) resulted in significant impairments in spatial learning and memory, along with reduced brain‐derived neurotrophic factor expression (PMID:34000322). Although these central nervous system deficits do not fully mirror the restless legs syndrome phenotype, they underscore ATRN’s importance in neurophysiology.

There is some conflicting evidence as the original exome sequencing study identified multiple candidate genes – with PCDHA3 emerging as a more plausible candidate in that context – thereby complicating the attribution of pathogenicity solely to ATRN. This overlapping evidence emphasizes that while ATRN variants co‐segregate with restless legs syndrome in one family, further validation is required.

In conclusion, ATRN presents as a potential genetic risk factor for restless legs syndrome, with a Limited level of clinical validity supported by both genetic and moderate functional evidence. Additional studies are warranted to substantiate the contribution of ATRN variants to the disease, which may eventually refine diagnostic decision‑making.

Key Take‑home: ATRN variants, although currently supported by limited evidence, represent a potential genetic marker for restless legs syndrome and merit further research to clarify their diagnostic and clinical utility.

References

• Movement disorders : official journal of the Movement Disorder Society • 2012 • Exome sequencing in a family with restless legs syndrome PMID:23192925
• Neuroscience • 2021 • Attractin Gene Deficiency in Rats Leads to Impairments in Both Activity and Spatial Learning and Memory PMID:34000322

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