MTX2 and Mandibuloacral Dysplasia Progeroid Syndrome

Mandibuloacral dysplasia progeroid syndrome (MDPS) is a rare autosomal recessive skeletal dysplasia featuring postnatal growth retardation, hypotonia, generalized lipodystrophy, progeroid skin changes, and characteristic facial dysmorphism including prominent eyes and mandibular hypoplasia. Biallelic loss-of-function variants in MTX2 underlie MDPS, expanding the differential beyond classical MAD types A and B. Genetic confirmation is essential for diagnosis and genetic counseling.

In a six-year-old patient with MDPS phenotype, whole-exome sequencing identified a novel homozygous splice-site variant c.543+1G>T resulting in skipping of exon 8 of MTX2, confirmed by cDNA analysis (PMID:36269149). This single unrelated proband represents the only report to date of MTX2 variants in MDPS, with no additional segregating affected relatives described.

The inheritance mode is autosomal recessive, consistent with biallelic null alleles leading to syndrome manifestation. The variant spectrum currently consists of this single splice-site alteration predicted to abolish normal splicing. No recurrent or founder alleles have been reported, and carrier frequencies remain undefined.

Functional studies in non-MDPS contexts demonstrate that MTX2 deficiency impairs mitochondrial structure and function, as Podocyte-specific Mtx2 knockout mice exhibit glomerular lesions, proteinuria, and disrupted mitochondrial complexes I and III, alongside elevated reactive oxygen species (ROS) and altered Sam50-CHCHD3-Mitofilin axis (PMID:38250156). These findings support a loss-of-function mechanism by which MTX2 null alleles lead to multi-system pathology.

No conflicting reports have disputed the role of MTX2 in MDPS; the concordance of transcript analysis and functional modeling strengthens the association. Additional unrelated cases and segregation data are needed to elevate the evidence beyond limited strength.

Key Take-home: Biallelic MTX2 splice-site variants cause autosomal recessive MDPS through a loss-of-function mechanism, meriting MTX2 in diagnostic gene panels for progeroid skeletal dysplasias.

References

• American journal of medical genetics. Part A • 2023 • A novel MTX2 gene splice site variant resulting in exon skipping, causing the recently described mandibuloacral dysplasia progeroid syndrome. PMID:36269149
• International journal of biological sciences • 2024 • Loss of MTX2 causes mitochondrial dysfunction, podocyte injury, nephrotic proteinuria and glomerulopathy in mice and patients. PMID:38250156

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