TMEM199 – congenital disorder of glycosylation

TMEM199 has been implicated in congenital disorders of glycosylation (CDG) with a hepatic predominance. Multiple independent studies report that patients harbor autosomal recessive pathogenic variants in TMEM199, with clinical presentations of abnormal glycosylation, elevated aminotransferases, and hypercholesterolemia (PMID:36706865, PMID:26833330). The overall gene–disease association is currently classified as Strong due to evidence from both case reports and multi‐patient studies.

The genetic evidence supports an autosomal recessive mode of inheritance. In the reported cases, affected individuals carry biallelic mutations with one recurrent pathogenic variant, c.92G>C (p.Arg31Pro), observed in several unrelated families. Additional variants identified include small deletions, splice‐site changes, and other missense mutations, further corroborating the allelic heterogeneity in TMEM199-related CDG (PMID:36706865, PMID:26833330).

Segregation analysis in familial studies has demonstrated consistent concordance of the TMEM199 variants with the disease phenotype. Notably, segregation in multiple unrelated families, including patients from southern Italy and Greece, reinforces the autosomal recessive inheritance pattern. The cumulative genetic findings from eight probands in case reports and four probands in multi‐patient studies provide robust support for the association (PMID:36706865, PMID:26833330).

Functional assessments have further strengthened the link between TMEM199 and CDG. Experimental studies, including metabolic labeling and mass spectrometry, consistently demonstrate abnormal N- and O-glycosylation in patient-derived fibroblasts. Rescue experiments via lentiviral transduction with wild-type TMEM199 reinstate proper glycosylation, thereby validating the pathogenic mechanism of impaired Golgi homeostasis in this disorder (PMID:26833330).

The molecular evidence is underscored by the recurrent detection of the specific variant c.92G>C (p.Arg31Pro) in multiple cohorts. This recurrent finding suggests a founder effect in the southern Mediterranean region and highlights the diagnostic importance of screening for this allele in patients with suggestive hepatic and glycosylation abnormalities (PMID:36706865).

The integration of genetic and functional data confirms a strong gene–disease association for TMEM199 in the context of congenital disorders of glycosylation. The convergence of multiple independent genetic events with consistent biochemical and cellular dysfunction solidifies its clinical significance and utility in diagnostic decision-making.

Key Take‑Home: TMEM199 deficiency should be considered in patients with congenital disorders of glycosylation and predominantly hepatic phenotypes, warranting its inclusion in targeted diagnostic panels.

References

• European Journal of Medical Genetics • 2023 • Higher frequency of TMEM199-CDG in the southern mediterranean area is associated with c.92G>C (p.Arg31Pro) mutation PMID:36706865
• American Journal of Human Genetics • 2016 • TMEM199 Deficiency Is a Disorder of Golgi Homeostasis Characterized by Elevated Aminotransferases, Alkaline Phosphatase, and Cholesterol and Abnormal Glycosylation PMID:26833330

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