Molecular characteristics:
MAN1B1 deficiency is inherited autosomal recessively. Homozygous or compound heterozygous pathogenic variations will lead to clinical findings. Over 40 patients of MAN1B1-CDG have been described up-to-date. Where approximately 500 variants of the gene nucleotide sequence are known, of which about 90 are pathogenic or likely pathogenic, most of them being missense variants.
The molecular underpinnings of this syndrome reside in pathogenic variants within the MAN1B1 gene, situated on chromosome 9q34.3. This gene encodes an α-1,2-mannosidase belonging to the glycosyl hydrolase family 47. Localized primarily in the Golgi apparatus, with some presence in the endoplasmic reticulum, this enzyme plays a pivotal role in N-glycosylation by taking a part in the maturation of glycans, as well as disposal of misfolded glycoproteins.
Pathophysiologic mechanism:
The α1,2-mannosidase enzyme catalyzes the removal of the terminal mannose from the middle branch of the Man9GlcNAc2 oligosaccharide (M9) linked to a nascent protein, where after the calnexin/calreticulin cycle, the ‘M8B’ structure is generated. Terminally misfolded or unassembled proteins are degraded by endoplasmic reticulum-associated protein degradation (ERAD), which consists of three steps, among which the first step is MAN1B1 recognizing a misfolded glycoprotein and yielding to extensive demannosylation by removing α1,2-linked mannoses from a oligosaccharide .
Defects in the MAN1B1 gene lead to impaired N-glycosylation of proteins, consequently disrupting the proper functioning and structure of these macromolecules, since glycoproteins with N-glycans lacking the terminal Man from the first (MAN8A) or third branch (M8C) are more likely degraded. Notably, MAN1B1 mutations have been shown to disrupt the Golgi apparatus morphology: Affecting the intricate organization and function of this crucial organelle involved in protein processing and modification; trigger desynchronization of the glycosylation process leading to the production of misfolded glycoproteins, and induce endoplasmic reticulum-associated protein degradation.
Overall, MAN1B1 mutations disrupt a critical step in N-glycosylation within the secretory pathway. This leads to a cascade of downstream effects, including protein misfolding, Golgi apparatus dysfunction, and potentially, ER stress and protein degradation. Understanding these intricate molecular mechanisms is crucial for elucidating the pathophysiology of the associated syndrome and developing potential therapeutic strategies. MAN1B1 deficiency is inherited in an autosomal recessive manner.
Diagnostic testing:
CDG-II are commonly detected using isoelectric focusing or capillary electrophoresis or HPLC analysis of transferrin showing decreased level of the tetrasialo glycoform and increased tri-, di-, mono- and a-sialo Trf glycoforms. Further characterization can be made by mass spectrometry.
Genetic analyses are required for definitive diagnosis. These analyses include:
• Single gene testing: Sequencing of MAN1B1 is performed to detect small intragenic deletions, insertions and missense, nonsense and splice site pathogenic variants in individuals with abnormal transferrin results and a strong clinical suspicion for a specific CDG subtype.
• Intellectual disability multigene panel -- The multigene panel includes MAN1B1 and other genes of interest.
• Comprehensive genomic testing: Whole exome sequencing and clinic exome sequencing is most commonly used if the patien’s clinical symptoms is insufficient for targeted gene testing.
MAN1B1