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Congenital disorders of glycosylation

Benedikt Hacker, Christoph Schultheiß, Michael Döring, Ursula Kurzik-Dumke
This study provides first insights into the involvement of hNOT/ALG3, the human counterpart of the Drosophila NOT and yeast ALG3 gene, in various putative molecular networks. HNOT/ALG3 encodes two translated transcripts encoding precursor proteins differing in their N-terminus and showing 33% identity with the yeast asparagine-linked glycosylation 3 (ALG3) protein. Experimental evidence for the functional homology of the proteins of fly and man in the N-glycosylation has still to be provided. In this study, using the yeast two-hybrid technique we identify 17 molecular partners of hNOT-1/ALG3-1...
March 14, 2018: Human Molecular Genetics
Asma Deeb, Abdulla Al Amoodi
We report a 4 years girl with congenital disorders of glycosylation (CDG) type Ib due to a novel homozygous mutation in MPI gene. She presented with diazoxide-responsive hyperinsulinemic hypoglycemia. CDG should be considered in unexplained hypoglycemia particularly in consanguineous families. Diagnosis enables monitoring/prevention of disease comorbidities and early effective treatment.
March 2018: Clinical Case Reports
Thatjana Gardeitchik, Jeroen Wyckmans, Eva Morava
Congenital disorders of glycosylation (CDG) and mitochondrial disorders have overlapping clinical features, including central nervous system, cardiac, gastrointestinal, hepatic, muscular, endocrine, and psychiatric disease. Specific abnormalities orienting the clinician toward the right diagnostic approach include abnormal fat distribution, coagulation abnormalities, together with anticoagulation abnormalities, hyperinsulinism, and congenital malformations in CDG. Diabetes, sensorineural deafness, and depression are very rare in CDG but common in mitochondrial disease...
April 2018: Pediatric Clinics of North America
Nurulamin Abu Bakar, Dirk J Lefeber, Monique van Scherpenzeel
Clinical glycomics comprises a spectrum of different analytical methodologies to analyze glycan structures, which provides insights into the mechanisms of glycosylation. Within clinical diagnostics, glycomics serves as a functional readout of genetic variants, and can form a basis for therapy development, as was described for PGM1-CDG. Integration of glycomics with genomics has resulted in the elucidation of previously unknown disorders of glycosylation, namely CCDC115-CDG, TMEM199-CDG, ATP6AP1-CDG, MAN1B1-CDG, and PGM1-CDG...
March 1, 2018: Journal of Inherited Metabolic Disease
José Rm Ceroni, Guilherme L Yamamoto, Rachel S Honjo, Chong A Kim, Maria R Passos-Bueno, Débora R Bertola
CHIME syndrome is an extremely rare autosomal recessive multisystemic disorder caused by mutations in PIGL. PIGL is an endoplasmic reticulum localized enzyme that catalyzes the second step of glycosylphosphatidylinositol (GPI) biosynthesis, which plays a role in the anchorage of cell-surface proteins including receptors, enzymes, and adhesion molecules. Germline mutations in other members of GPI and Post GPI Attachment to Proteins (PGAP) family genes have been described and constitute a group of diseases within the congenital disorders of glycosylation...
February 19, 2018: Genetics and Molecular Biology
Katsuki Mukaigasa, Tadayuki Tsujita, Vu Thanh Nguyen, Li Li, Hirokazu Yagi, Yuji Fuse, Yaeko Nakajima-Takagi, Koichi Kato, Masayuki Yamamoto, Makoto Kobayashi
Nrf2 plays critical roles in animals' defense against electrophiles and oxidative stress by orchestrating the induction of cytoprotective genes. We previously isolated the zebrafish mutant it768 , which displays up-regulated expression of Nrf2 target genes in an uninduced state. In this paper, we determine that the gene responsible for it768 was the zebrafish homolog of phosphomannomutase 2 (Pmm2), which is a key enzyme in the initial steps of N-glycosylation, and its mutation in humans leads to PMM2-CDG (congenital disorders of glycosylation), the most frequent type of CDG...
February 22, 2018: Proceedings of the National Academy of Sciences of the United States of America
Eun-Kyung Choi, Trang-Tiffany Nguyen, Neil Gupta, Shigeki Iwase, Young Ah Seo
SLC39A8 encodes ZIP8, a divalent metal ion transporter. Mutations in the SLC39A8 gene are associated with congenital disorder of glycosylation type II and Leigh syndrome. Notably, affected patients with both disorders exhibited severe manganese (Mn) deficiency. The cellular function of human SLC39A8 (hSLC39A8) and the mechanisms by which mutations in this protein lead to human diseases are unclear. Herein, we show that hSLC39A8 mediates54 Mn uptake by the cells, and its expression is regulated by Mn. While expression of wild-type hSLC39A8 increased54 Mn uptake activity, disease-associated mutations abrogated the ability of the transporter to mediate Mn uptake into the cells, thereby providing a causal link to severe Mn deficiency...
February 16, 2018: Scientific Reports
Nina Ondruskova, Tomas Honzik, Hana Kolarova, Zuzana Pakanova, Jan Mucha, Jiri Zeman, Hana Hansikova
INTRODUCTION: Apolipoprotein C-III (ApoC-III) is a mostly liver-derived serum O-glycoprotein, which is used, along with an N-glycoprotein transferrin (TF), as a marker in the biochemical screening for congenital disorders of glycosylation (CDG). However, it is increasingly evident that secondary glycosylation abnormalities might occur in other, non-CDG metabolic diseases. MATERIAL AND METHODS: Here we examined the glycosylation status of serum TF and Apo-CIII by isoelectric focusing, SDS-PAGE and MALDI TOF mass spectrometry in our group of 24 patients with various types of glycogen storage disorders (GSD; types 0, Ia, nonIa, III and IX)...
February 1, 2018: Metabolism: Clinical and Experimental
Bianca Dimitrov, Nastassja Himmelreich, Agnes L Hipgrave Ederveen, Christian Lüchtenborg, Jürgen G Okun, Maximilian Breuer, Anna-Marlen Hutter, Matthias Carl, Luca Guglielmi, Andrea Hellwig, Kai Christian Thiemann, Markus Jost, Verena Peters, Christian Staufner, Georg F Hoffmann, Annette Hackenberg, Nagarajan Paramasivam, Stefan Wiemann, Roland Eils, Matthias Schlesner, Sabine Strahl, Britta Brügger, Manfred Wuhrer, G Christoph Korenke, Christian Thiel
Congenital disorders of glycosylation (CDG) are genetic defects in the glycoconjugate biosynthesis. >100 types of CDG are known, most of them cause multi-organ diseases. Here we describe a boy whose leading symptoms comprise cutis laxa, pancreatic insufficiency and hepatosplenomegaly. Whole exome sequencing identified the novel hemizygous mutation c.542T>G (p.L181R) in the X-linked ATP6AP1, an accessory protein of the mammalian vacuolar H+-ATPase, which led to a general N-glycosylation deficiency. Studies of serum N-glycans revealed reduction of complex sialylated and appearance of truncated diantennary structures...
January 27, 2018: Molecular Genetics and Metabolism
R Francisco, C Pascoal, D Marques-da-Silva, E Morava, G A Gole, D Coman, J Jaeken, Vanessa Dos Reis Ferreira
Congenital disorders of glycosylation (CDG) are a rapidly growing family comprising >100 genetic diseases. Some 25 CDG are pure O-glycosylation defects. Even among this CDG subgroup, phenotypic diversity is broad, ranging from mild to severe poly-organ/system dysfunction. Ophthalmic manifestations are present in 60% of these CDG. The ophthalmic manifestations in N-glycosylation-deficient patients have been described elsewhere. The present review documents the spectrum and incidence of eye disorders in patients with pure O-glycosylation defects with the aim of assisting diagnosis and management and promoting research...
February 1, 2018: Journal of Inherited Metabolic Disease
David Beeson, Judith Cossins, Pedro Rodriguez-Cruz, Susan Maxwell, Wei-Wei Liu, Jacqueline Palace
The congenital myasthenic syndromes (CMS) are hereditary disorders of neuromuscular transmission. The number of cases recognized, at around 1:100,000 in the United Kingdom, is increasing with improved diagnosis. The advent of next-generation sequencing has facilitated the discovery of many genes that harbor CMS-associated mutations. An emerging group of CMS, characterized by a limb-girdle pattern of muscle weakness, is caused by mutations in genes that encode proteins involved in the initial steps of the N-linked glycosylation pathway, which is surprising, since this pathway is found in all mammalian cells...
January 24, 2018: Annals of the New York Academy of Sciences
Ruo-Hao Wu, Dong-Fang Li, Wen-Ting Tang, Kun-Yin Qiu, Yu Li, Xiong-Yu Liao, Dan-Xia Tang, Li-Jun Qin, Bing-Qing Deng, Xiang-Yang Luo
BACKGROUND: Atrial septal defect often become more severe when encountered in genetic syndromes. Congenital disorder of glycosylation type 1a is an inherited metabolic disorder associated with mutations in PMM2 gene and can affect almost all organs. Cardiac abnormalities vary greatly in congenital disorder of glycosylation type 1a and congenital heart defects have already been reported, but there is little knowledge about the effect of this inherited disorder on an existing congenital heart defect...
January 24, 2018: Journal of Medical Case Reports
Bobby G Ng, Gege Xu, Nandini Chandy, Joan Steyermark, Deepali N Shinde, Kelly Radtke, Kimiyo Raymond, Carlito B Lebrilla, Ali AlAsmari, Sharon F Suchy, Zöe Powis, Eissa Ali Faqeih, Susan A Berry, David F Kronn, Hudson H Freeze
Fucosyltransferase 8 (FUT8) encodes a Golgi-localized α1,6 fucosyltransferase that is essential for transferring the monosaccharide fucose into N-linked glycoproteins, a process known as "core fucosylation." Here we describe three unrelated individuals, who presented with intrauterine growth retardation, severe developmental and growth delays with shortened limbs, neurological impairments, and respiratory complications. Each underwent whole-exome sequencing and was found to carry pathogenic variants in FUT8...
January 4, 2018: American Journal of Human Genetics
Toshihiko Kitajima, Wei Xue, Yi-Shi Liu, Chun-Di Wang, Si-Si Liu, Morihisa Fujita, Xiao-Dong Gao
Oligosaccharyltransferases (OSTs) mediate the en bloc transfer of N-glycan intermediates onto the asparagine residue in glycosylation sequons (N-X-S/T, X≠P). These enzymes are typically heteromeric complexes composed of several membrane-associated subunits, in which STT3 is highly conserved as a catalytic core. Metazoan organisms encode two STT3 genes (STT3A and STT3B) in their genome, resulting in the formation of at least two distinct OST isoforms consisting of shared subunits and complex specific subunits...
December 28, 2017: FEBS Journal
Reza Maroofian, Moniek Riemersma, Lucas T Jae, Narges Zhianabed, Marjolein H Willemsen, Willemijn M Wissink-Lindhout, Michèl A Willemsen, Arjan P M de Brouwer, Mohammad Yahya Vahidi Mehrjardi, Mahmoud Reza Ashrafi, Benno Kusters, Tjitske Kleefstra, Yalda Jamshidi, Mojila Nasseri, Rolph Pfundt, Thijn R Brummelkamp, Mohammad Reza Abbaszadegan, Dirk J Lefeber, Hans van Bokhoven
BACKGROUND: The phenotypic severity of congenital muscular dystrophy-dystroglycanopathy (MDDG) syndromes associated with aberrant glycosylation of α-dystroglycan ranges from the severe Walker-Warburg syndrome or muscle-eye-brain disease to mild, late-onset, isolated limb-girdle muscular dystrophy without neural involvement. However, muscular dystrophy is invariably found across the spectrum of MDDG patients. METHODS: Using linkage mapping and whole-exome sequencing in two families with an unexplained neurodevelopmental disorder, we have identified homozygous and compound heterozygous mutations in B3GALNT2...
December 22, 2017: Genome Medicine
Yoon-Myung Kim, Go Hun Seo, Euiseok Jung, Ja-Hyun Jang, Sook Za Kim, Beom Hee Lee
Over 100 types of congenital disorders of glycosylation (CDG) have been reported and the number is rapidly increasing. However, each type is very rare and is problematic to diagnose. Mannosyl-oligosaccharide glucosidase (MOGS)-CDG (CDG type IIb) is an extremely rare CDG that has only been reported in three patients from two unrelated families. Using targeted exome sequencing, we identified another patient affected by this condition. This patient had increased serum trisialotransferrin levels. Importantly, a review of the features of all four patients revealed the recognizable clinical hallmarks of MOGS-CDG...
March 2018: Journal of Human Genetics
Ruqaiah Altassan, Peter Witters, Zubaida Saifudeen, Dulce Quelhas, Jaak Jaeken, Elena Levtchenko, David Cassiman, Eva Morava
Phosphomannomutase 2 deficiency (PMM2-CDG) is the most common N-linked glycosylation disorder. The majority of patients present with a multisystem phenotype, including central nervous system involvement, hepatopathy, gastrointestinal and cardiac symptoms, endocrine dysfunction and abnormal coagulation. Renal abnormalities including congenital malformations and altered renal function are part of the multisystem manifestations of congenital disorders of glycosylation. We reviewed the literature on 933 patients with molecularly and/or enzymatically confirmed PMM2 deficiency to evaluate the incidence of renal involvement in PMM2-CDG...
March 2018: Molecular Genetics and Metabolism
Coralie Ruel, Marco Morani, Arnaud Bruneel, Christophe Junot, Myriam Taverna, François Fenaille, Nguyet Thuy Tran
ApolipoproteinC-III (ApoC-III) is a human plasma glycoprotein whose O-glycosylation can be altered as a result of congenital disorders of glycosylation (CDG). ApoC-III exhibits three major glycoforms whose relative quantification is of utmost importance for the diagnosis of CDG patients. Considering the very close structures of these glycoforms and their tendency to adsorb on the capillary, a thorough optimization of capillary electrophoresis (CE) parameters including preconditioning and in-between rinsing procedures was required to efficiently separate all the ApoC-III glycoforms...
January 12, 2018: Journal of Chromatography. A
M Saifur Rahman, Md Khaledur Rahman, M Kaykobad, M Sohel Rahman
The Golgi Apparatus (GA) is a key organelle for protein synthesis within the eukaryotic cell. The main task of GA is to modify and sort proteins for transport throughout the cell. Proteins permeate through the GA on the ER (Endoplasmic Reticulum) facing side (cis side) and depart on the other side (trans side). Based on this phenomenon, we get two types of GA proteins, namely, cis-Golgi protein and trans-Golgi protein. Any dysfunction of GA proteins can result in congenital glycosylation disorders and some other forms of difficulties that may lead to neurodegenerative and inherited diseases like diabetes, cancer and cystic fibrosis...
January 2018: Artificial Intelligence in Medicine
Shanti Balasubramaniam, Lisa G Riley, Anand Vasudevan, Mark J Cowley, Velimir Gayevskiy, Carolyn M Sue, Caitlin Edwards, Edward Edkins, Reimar Junckerstorff, C Kiraly-Borri, P Rowe, J Christodoulou
Vici syndrome is a rare, under-recognised, relentlessly progressive congenital multisystem disorder characterised by five principal features of callosal agenesis, cataracts, cardiomyopathy, combined immunodeficiency and oculocutaneous hypopigmentation. In addition, three equally consistent features (profound developmental delay, progressive failure to thrive and acquired microcephaly) are highly supportive of the diagnosis. Since its recognition as a distinct entity in 1988, an extended phenotype with sensorineural hearing loss, skeletal myopathy and variable involvement of virtually any organ system, including the lungs, thyroid, liver and kidneys, have been described...
November 21, 2017: JIMD Reports
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