TMEM165 deficiency causes a congenital disorder of glycosylation.

Protein glycosylation is a complex process that depends not only on the activities of several enzymes and transporters but also on a subtle balance between vesicular Golgi trafficking, compartmental pH, and ion homeostasis. Through a combination of autozygosity mapping and expression analysis in two siblings with an abnormal serum-transferrin isoelectric focusing test (type 2) and a peculiar skeletal phenotype with epiphyseal, metaphyseal, and diaphyseal dysplasia, we identified TMEM165 (also named TPARL) as a gene involved in congenital disorders of glycosylation (CDG). The affected individuals are homozygous for a deep intronic splice mutation in TMEM165.

Screening for OST deficiencies in unsolved CDG-I patients.

Congenital Disorders of Glycosylation (CDG) are a group of inherited disorders caused by deficiencies in glycosylation. Since 1980, 14 CDG type I (CDG-I) defects have been identified in the endoplasmic reticulum, all affecting the assembly of the oligosaccharide precursor. However, the number of unsolved CDG-I (CDG-Ix) patients displaying protein hypoglycosylation in combination with an apparently normal assembly of the oligosaccharide precursor is currently expanding.

Long-term evolution of eight Spanish patients with CDG type Ia: typical and atypical manifestations.

Congenital disorder of glycosylation Ia (CDG-Ia) is a metabolic disease with a broad spectrum of clinical signs, including recently described mild phenotypes. Our aim was to describe the clinical presentation and follow-up of eight CDG-Ia patients highlighting atypical features and aspects of evolution of the disease. CDG diagnosis was confirmed by enzymatic analysis of phosphomannomutase (PMM2) and molecular studies of the PMM2 gene.

The normal phenotype of Pmm1-deficient mice suggests that Pmm1 is not essential for normal mouse development.

Phosphomannomutases (PMMs) are crucial for the glycosylation of glycoproteins. In humans, two highly conserved PMMs exist: PMM1 and PMM2. In vitro both enzymes are able to convert mannose-6-phosphate (mannose-6-P) into mannose-1-P, the key starting compound for glycan biosynthesis.