MTX2 was first reported in relation to autosomal recessive mandibuloacral dysplasia progeroid syndrome (MDPS; OMIM # 619127) in 2020 (Elouej et al., PMID: 32917887). MDPS is a severe laminopathy-like disorder characterized by by dysmorphic facial features, lipodystrophy, skin changes, clavicular hypoplasia, acral osteolysis, and normal intelligence with an unknown prevalence. MTX2 encodes the metaxin 2 protein which is located at the outer mitochondrial membrane (OMM) and faces the cytosolic compartment through direct interaction with its partner Metaxin-1 (MTX1). It is involved in protein translocation into mitochondria.
Evidence supporting this gene-disease relationship includes case-level data, segregation data and experimental data. Nine unique loss of function variants (frameshift, start loss, splice variants) that have been reported in 8 probands in 3 publications are included in this curation (PMID: 32917887; Dogan et al 2022, PMID: 36269149; Li et al 2024, PMID: 38250156). The mechanism of pathogenicity appears to be loss of function. This gene-disease relationshipis also supported by expression studies, t animal models, rescue experiments, and in-vitro functional assays. Experimentally, MTX2 deficiency is demostrated to result in loss of Metaxin-1 (MTX1) and mitochondrial dysfunction, including network fragmentation and oxidative phosphorylation impairment, which may account for poor growth, hypotonia, muscle weakness, skeletal abnormalities, nephrotic proteinuria and glomerulopathy.
In summary, there is definitive evidence supporting the relationship between MTX2 and autosomal recessive mandibuloacral dysplasia progeroid syndrome. 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 Syndromic Disorders GCEP on the meeting date June 5, 2024 (SOP Version 10).
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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