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FB2026_01
,
released March 12, 2026
This report describes congenital disorders of glycosylation, type Ia (CDG1A), which is a subtype of congenital disorders of glycosylation, type I; CDG1A exhibits autosomal recessive inheritance. The human gene implicated in this disease is phosphomannomutase 2 (PMM2), which is required for synthesis of precursors involved in the incorporation of mannose into oligosaccharides. There is a single high-scoring fly ortholog, Dmel\Pmm2, for which loss-of-function alleles, RNAi targeting constructs, and alleles caused by insertional mutagenesis have been generated. There is a second human gene orthologous to Dmel\Pmm2, PMM1.
The human PMM2 gene has not been introduced into flies.
Animals homozygous for amorphic mutations of Dmel\Pmm2 die during the second larval instar stage; first instar larvae exhibit locomotor and neuroanatomy defects. N-linked glycans in mutant animals were analyzed by mass spectrometry (MS): all detected N-glycans (not only mannose-containing glycans) exhibited significant reductions; levels of free oligosaccharides increased. These observations are consistent with a global suppression of glycoprotein glycosylation. A single physical interaction has been described for Dmel\Pmm2; see below and in the Pmm2 gene report.
A variant implicated in human disease has been introduced into flies, but has not been characterized. Variant(s) implicated in human disease (analogous mutation in fly gene): F125L in the fly Pmm2 gene (corresponds to F119L in the human PMM2 gene).
[updated Oct. 2019 by FlyBase; FBrf0222196]
[CONGENITAL DISORDER OF GLYCOSYLATION, TYPE Ia; CDG1A](https://omim.org/entry/212065)
[PHOSPHOMANNOMUTASE 2; PMM2](https://omim.org/entry/601785)
Clinical presentation and course are highly variable, ranging from infants who die in the first year of life to mildly involved adults. [Gene Reviews, PMM2-CDG (CDG-Ia); 2017.06.23]
CDG can affect any part of the body; many subtypes of CDG have a significant neurological component involving the central nervous system. Common neurological symptoms include diminished muscle tone (hypotonia), seizures, deficits in attaining developmental milestones (developmental disability), varying degrees of cognitive impairment, and underdevelopment of the cerebellum (cerebellar hypoplasia), which can cause problems with balance and coordination. [from NORD, Congenital Disorders of Glycosylation; 2017.06.23]
CDG1A is multisystem disorder characterized by defective glycosylation of glycoproteins and glycolipids. It usually presents as a severe disorder in the neonatal period. There is a severe encephalopathy with axial hypotonia, abnormal eye movement, and pronounced psychomotor retardation, as well as peripheral neuropathy, cerebellar hypoplasia, and retinitis pigmentosa. There is a 20% lethality in the first year of life due to severe infections, liver insufficiency, or cardiomyopathy (Matthijs, et al., 1999; pubmed:10527672). [from MIM:212065; 2017.06.23]
Congenital disorder of glycosylation type Ia (CDG Ia, CDG1A) is caused by homozygous or compound heterozygous mutation in the gene encoding phosphomannomutase-2 (PMM2). [from MIM:212065; 2017.06.23]
Phosphomannomutase 2 (PMM2) catalyzes the isomerization of mannose 6-phosphate to mannose 1-phosphate, which is a precursor to GDP-mannose; GDP-mannose is necessary for the synthesis of dolichol-P-oligosaccharides. Synthesis of the GDP-mannose and dolichol-phosphate-mannose are required for a number of critical mannosyl transfer reactions. [Gene Cards, PMM2; 2017.06.23]
Many to one: 2 human to 1 Drosophila. The second human gene is PMM1.
High-moderate-scoring ortholog of PMM2; moderate-scoring ortholog of PMM1 (1 Drosophila to 2 human). Deml\Pmm2 shares 56% identity and 75% similarity with PMM2; it shares 36% identity and 45% similarity with PMM1.