MTMR2 was first reported in relation to autosomal recessive demyelinating hereditary motor and sensory neuropathy, and more specifically Charcot Marie Tooth type 4B1 in 2000 (Bolino et al., 2000; PMID: 10802647). The phenotype associated with MTMR2 including vocal paresis, severe neuropathy at an early onset (adolescents), and pathologically with the presence of myelin outfolding (reviewed in Tazir et al., 2013; PMID: 23781959). At least 25 unique variants, including missense, nonsense, frameshift, and indels have been reported in humans (reviewed in Pareyson et al., 2019, PMID: 31070812 and per the Inherited Neuropathy Variant Database). There are variant databases describing MTMR2 variants of interest in neuropathy, including (1) the Inherited Neuropathy Variant Database (URL: http://hihg.med.miami.edu/code/http/cmt/public_html/index.html#/) and (2) the MTMR2 LOVD database (https://databases.lovd.nl/shared/genes/MTMR2). Evidence supporting this gene-disease relationship includes case-level data, segregation and experimental data. This gene-disease relationship has been well studied and the case-level data does not reflect all published studies. This gene-disease relationship is supported by expression studies, protein interaction, animal models and rescue models. MTMR2 has 18 exons, and produces several transcripts due to two start sites (exon 1 and exon 3). Studies have indicated that nonsense mutations may not result in loss of protein expression, as the truncated proteins remain expressed in patient cells (Prevatali et al., 2003 PMID:1335693). The molecular mechanism is predicted to be loss of phosphatase activity (reviewed in Raghu et al., 2019; PMID: 31507376; Tazir et al., 2013; PMID: 23781959). In summary, MTMR2 is DEFINITIVELY associated with autosomal recessive demyelinating hereditary motor and sensory neuropathy. This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time. This classification was approved by the ClinGen Charcot Marie Tooth Gene Curation Expert Panel on Feb 11, 2020.
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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