ATL3 was first reported in relation to autosomal dominant Charcot-Marie-Tooth Disease in 2014 (Kornak et al., PMID: 24459106). ATL3 encodes for the endoplasmic reticulum (ER) membrane shaping protein, atlastin 3. Two recurrent missense variants, Y192C and P338R, have been reported in five autosomal dominant families from four different publications (PMIDs: 24459106, 34090020, 24736309, 30680846). All reported cases are described with axonal sensory neuropathy (HSN). Clinical presentation includes sensory disturbances in the distal parts of the lower limbs, painless injuries and foot ulcerations. Case-level variant and experimental evidence support the gene-disease relationship. Expression of the ATL3 mutant Y192C in cell culture led to protein aggregates and disruption of the endoplasmic reticulum network (PMID: 24459106). Expression of both mutants, Y192C and P338R, caused disruption of the ER connectivity and loss of ER fusion efficiency in transfected cells (PMID: 29768202). In situ hybridization analysis in mouse tissues show high expression of ATL3 in dorsal root ganglion (DRG), in line with the major site of the pathology (PMID:24459106). ATL3 can physically interact with ATL1, which has also been associated with HSN (PMID: 24459106). In addition, ATL3 performs a biochemical function shared with ATL1 in ER structure maintenance (PMID: 27619977). Analysis of patient fibroblasts revealed abnormal ER network and altered mitochondrial distribution and dynamics (PMIDs: 29768202 and 30339187). Although there is strong genetic and experimental supporting evidence available, the lack of additional families and an animal model limits the final classification to MODERATE.
The GenCC data are available free of restriction under a CC0 1.0 Universal (CC0 1.0) Public Domain Dedication. The GenCC requests that you give attribution to GenCC and the contributing sources whenever possible and appropriate. The accepted Flagship manuscript is now available from Genetics in Medicine (https://www.gimjournal.org/article/S1098-3600(22)00746-8/fulltext).
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