MAN1B1 Deficiency: An Unexpected CDG-II

Daisy Rymen,Philippa Mills,Domenico Garozzo,François Foulquier,Ali Cansu,Miguel Gonçalves-Rocha,María B Millón,Esmeralda Martins,Peter Clayton,Jaak Jaeken,Marie-Cécile Nassogne,Luisa Sturiale,Valérie Race,Gert Matthijs,Dulce Quelhas,Carla G Asteggiano,Romain Peanne,Haluk Topaloglu

doi:10.1371/journal.pgen.1003989

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.

Highlights

Congenital Disorders of Glycosylation (CDG) are a group of genetic diseases, due to deficient protein and lipid glycosylation [1]
The resulting glycoproteins serve many critical roles in metabolism. The importance of this pathway is illustrated by a group of diseases called Congenital Disorders of Glycosylation (CDG)
We demonstrated that mutations in MAN1B1, a gene formerly linked to non-syndromic intellectual disability, cause CDG

Summary

Introduction

Congenital Disorders of Glycosylation (CDG) are a group of genetic diseases, due to deficient protein and lipid glycosylation [1]. Over the last few years, massive parallel sequencing techniques have permitted to identify the underlying genetic defect in a growing number of diseases. In case of CDG, exome sequencing led to the discovery of 7 novel disorders in less than 2 years [3]. A prerequisite for export of a protein out of the ER and its further transport through the secretory pathway is the adaptation of a native folding state [4]. A quality control system has evolved to ensure that only properly folded proteins reach the plasma membrane. Glycoproteins unable to acquire a correct conformation will be recognized as terminally misfolded and marked for degradation by demannosylation of their glycan moiety

Methods

Results

Discussion

Conclusion