TMEM165 – TMEM165-Congenital Disorder of Glycosylation

TMEM165-CDG is an autosomal recessive multisystem glycosylation disorder characterized by skeletal dysplasia, nephrotic syndrome, facial dysmorphism, ventriculomegaly and feeding difficulties. The gene-disease association meets a ClinGen Moderate level of evidence based on 5 probands across 3 families ([PMID:23430531]; [PMID:26238249]; [PMID:38013006]), limited segregation (1 affected relative), and concordant functional assays demonstrating TMEM165’s role in Golgi Ca²⁺/Mn²⁺ homeostasis.

Genetic evidence supports an autosomal recessive inheritance. Three patients from two families share a deep intronic homozygous mutation c.792+182G>A ([PMID:23430531]), one proband carries a novel homozygous missense c.928G>C (p.Ala310Pro) ([PMID:38013006]), and an additional singleton was described with clinical TMEM165-CDG features ([PMID:26238249]). Segregation of the deep intronic variant in sibships provides limited additional support (1 affected relative). The variant spectrum includes intronic splice and missense alleles; c.928G>C (p.Ala310Pro) is functionally unstable and pathogenic.

Functional studies elucidate a loss-of-function mechanism via impaired Golgi manganese and calcium transport. Expression of human TMEM165 rescues Ca²⁺ sensitivity in yeast gdt1Δ cells and restores pH/Ca²⁺ homeostasis ([PMID:23569283]), while knockout HEK293 models exhibit hypogalactosylation corrected by Mn²⁺ or galactose supplementation. Structural modeling confirms TMEM165’s acidic cation-binding site crucial for activity, and disease-associated mutations disrupt this motif ([PMID:37416081]). TMEM165 localizes to Golgi membranes, and pathogenic variants alter its stability and subcellular targeting.

Therapeutic rescue studies demonstrate that combined oral Mn²⁺ and D-galactose fully suppress N-, O- and GAG hypoglycosylation in a patient with c.928G>C (p.Ala310Pro) and improve clinical and biochemical parameters ([PMID:38013006]). Similarly, oral galactose supplementation in deep intronic c.792+182G>A patients enhances transferrin glycoforms and coagulation factors, confirming functional rescue in vivo ([PMID:28323990]). These interventions underscore TMEM165-CDG’s treatable nature.

Together, genetic and experimental evidence delineate TMEM165 deficiency as a distinct CDG subtype mediated by loss of Golgi Mn²⁺/Ca²⁺ antiporter function. While additional rare variants and splice isoforms exist, current data suffice for a Moderate ClinGen classification. Key Take-home: TMEM165-CDG is AR and clinically actionable, with genetic diagnosis guiding Mn²⁺/galactose therapy to restore glycosylation.

References

• JIMD reports • 2013 • Bone Dysplasia as a Key Feature in Three Patients with a Novel Congenital Disorder of Glycosylation (CDG) Type II Due to a Deep Intronic Splice Mutation in TMEM165. PMID:23430531
• JIMD reports • 2016 • TMEM165 Deficiency: Postnatal Changes in Glycosylation. PMID:26238249
• Translational research : the journal of laboratory and clinical medicine • 2024 • Efficacy of oral manganese and D-galactose therapy in a patient bearing a novel TMEM165 variant. PMID:38013006
• Proceedings of the National Academy of Sciences of the United States of America • 2013 • Newly characterized Golgi-localized family of proteins is involved in calcium and pH homeostasis in yeast and human cells. PMID:23569283
• The Journal of clinical endocrinology and metabolism • 2017 • Galactose Supplementation in Patients With TMEM165-CDG Rescues the Glycosylation Defects. PMID:28323990
• The Journal of biological chemistry • 2020 • The human Golgi protein TMEM165 transports calcium and manganese in yeast and bacterial cells. PMID:32047108

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