DGAT2 – Charcot-Marie-Tooth Disease

DGAT2 (HGNC:16940) has been implicated in autosomal-dominant axonal Charcot-Marie-Tooth disease (MONDO:0015626) based on a single Korean pedigree. Clinical validity is classified as Limited given one family with two affected individuals and no additional unrelated cases ([PMID:26786738]).

Genetic evidence supports an autosomal-dominant inheritance. Exome sequencing identified a de novo missense variant, c.667T>C (p.Tyr223His), in two affected family members ([PMID:26786738]). No further segregation beyond the probands was observed.

Functional studies demonstrate that overexpression of DGAT2 p.Tyr223His in mouse motor neuron cells significantly inhibits cell proliferation, and expression of the variant in zebrafish embryos reduces peripheral axonal branching, consistent with a dominant-negative mechanism ([PMID:26786738]).

No conflicting reports have been published to date that refute this association.

Overall, DGAT2 c.667T>C (p.Tyr223His) is a plausible cause of AD axonal CMT with concordant functional data. Further case series and segregation analyses are needed to substantiate this gene–disease link. Key Take-home: DGAT2 variant testing may inform molecular diagnosis of early-onset axonal CMT.

References

• Human Mutation • 2016 • DGAT2 Mutation in a Family with Autosomal-Dominant Early-Onset Axonal Charcot-Marie-Tooth Disease PMID:26786738

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