MAN1B1 Deficiency: An Unexpected CDG-II

Abstract

Congenital disorders of glycosylation (CDG) are a group of rare metabolic diseases, due to impaired protein and lipid glycosylation. In the present study, exome sequencing was used to identify MAN1B1 as the culprit gene in an unsolved CDG-II patient. Subsequently, 6 additional cases with MAN1B1-CDG were found. All individuals presented slight facial dysmorphism, psychomotor retardation and truncal obesity. Generally, MAN1B1 is believed to be an ER resident alpha-1,2-mannosidase acting as a key factor in glycoprotein quality control by targeting misfolded proteins for ER-associated degradation (ERAD). However, recent studies indicated a Golgi localization of the endogenous MAN1B1, suggesting a more complex role for MAN1B1 in quality control. We were able to confirm that MAN1B1 is indeed localized to the Golgi complex instead of the ER. Furthermore, we observed an altered Golgi morphology in all patients' cells, with marked dilatation and fragmentation. We hypothesize that part of the phenotype is associated to this Golgi disruption. In conclusion, we linked mutations in MAN1B1 to a Golgi glycosylation disorder. Additionally, our results support the recent findings on MAN1B1 localization. However, more work is needed to pinpoint the exact function of MAN1B1 in glycoprotein quality control, and to understand the pathophysiology of its deficiency.

ERManI (Endoplasmic Reticulum Class I α-Mannosidase) Is Required for HIV-1 Envelope Glycoprotein Degradation via Endoplasmic Reticulum-associated Protein Degradation Pathway

“…The formation of a disulfide bond between these residues was demonstrated in the yeast Mns1, which was proposed to stabilize the protein (38). Moreover, R334C and E397K mutations are identified in nonsyndromic autosomal-recessive intellectual disability (NS-ARID) patients (39), and the R334C mutation is also found in the congenital disorders of glycosylation (40). The E397K mutation was found to reduce the ERManI expression, and the R334C mutation was found to reduce the enzyme efficiency by ϳ100% (39).…”

Genetic Defects Underlie the Non-syndromic Autosomal Recessive Intellectual Disability (NS-ARID)

“…This mutation was later on identified in two Turkish families and a family of unknown origin with congenital disorders of glycosylation by Rymen et al [62] and Van Scherpenzeel et al [63], as well as in the affected children of a Turkish family with syndromic ID by Hoffjan et al, [64]. They further suggested that this mutation in MAN1B1 leads to a syndromic disorder rather than NS-ARID.…”

Clinical utility gene card for: MAN1B1 defective congenital disorder of glycosylation

“…[1][2][3] (www.lovd.nl/MAN1B1). The standard reference sequence indicating reported variants (ENSG00000177239) and a reference for exon numbering (ENST00000474902) can be found at http://www.…”

“…[1][2][3] The frequency and the prevalence of the disease are not known. Comment: MAN1B1-CDG is an autosomal recessive disorder.…”

“…Most patients also presented abnormal speech development and hypotonia. [1][2][3] In the majority of patients there was facial dysmorphism (mainly down-slanting palpebral fissures, prominent eyebrows with lateral thinning, prominent bulbous nose tip, tent-shaped mouth with thin upper lip, and large ears) and truncal obesity. Behavioural problems have been reported in about half of the patients, particularly verbal and physical aggression, inappropriate sexual behaviour and overeating.…”