COG1-congenital disorders of glycosylation: Milder presentation and review.

Congenital disorders of glycosylation (CDG) are a heterogeneous group of genetic defects in glycoprotein and glycolipid glycan synthesis and attachment. A CDG subgroup are defects in the conserved oligomeric Golgi complex encoded by eight genes, COG1-COG8. Pathogenic variants in all genes except the COG3 gene have been reported. COG1-CDG has been reported in five patients. We report a male with neonatal seizures, dysmorphism, hepatitis and a type 2 serum transferrin isoelectrofocusing. Exome sequencing identified a homozygous COG1 variant (NM_018714.3: c.2665dup: p.[Arg889Profs*12]), which has been reported previously in one patient. We review the reported patients.

Encephalopathy caused by novel mutations in the CMP-sialic acid transporter, SLC35A1.

Transport of activated nucleotide-sugars into the Golgi is critical for proper glycosylation and mutations in these transporters cause a group of rare genetic disorders termed congenital disorders of glycosylation. We performed exome sequencing on an individual with a profound neurological presentation and identified rare compound heterozygous mutations, p.Thr156Arg and p.Glu196Lys, in the CMP-sialic acid transporter, SLC35A1. Patient primary fibroblasts and serum showed a considerable decrease in the amount of N- and O-glycans terminating in sialic acid. Direct measurement of CMP-sialic acid transport into the Golgi showed a substantial decrease in overall rate of transport. Here we report the identification of the third patient with CMP-sialic acid transporter deficiency, who presented with severe neurological phenotype, but without hematological abnormalities.

MAN1B1 deficiency: an unexpected CDG-II.

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.

Identification and functional analyses of CBS alleles in Spanish and Argentinian homocystinuric patients.

Homocystinuria due to CBS deficiency is a rare autosomal recessive disorder characterized by elevated plasma levels of homocysteine (Hcy) and methionine (Met). Here we present the analysis of 22 unrelated patients of different geographical origins, mainly Spanish and Argentinian. Twenty-two different mutations were found, 10 of which were novel. Five new mutations were missense and five were deletions of different sizes, including a 794-bp deletion (c.532-37_736 + 438del794) detected by Southern blot analysis. To assess the pathogenicity of these mutations, seven were expressed heterologously in Escherichia coli and their enzyme activities were assayed in vitro, in the absence and presence of the CBS activators PLP and SAM. The presence of the mutant proteins was confirmed by Western blotting. Mutations p.M173del, p.I278S, p.D281N, and p.D321V showed null activity in all conditions tested, whereas mutations p.49L, p.P200L and p.A446S retained different degrees of activity and response to stimulation. Finally, a minigene strategy allowed us to demonstrate the pathogenicity of an 8-bp intronic deletion, which led to the skipping of exon 6. In general, frameshifting deletions correlated with a more severe phenotype, consistent with the concept that missense mutations may recover enzymatic activity under certain conditions.

Multiple osteochondromas: mutation update and description of the multiple osteochondromas mutation database (MOdb).

Multiple osteochondromas (MO) is an autosomal dominant skeletal disease characterized by the formation of multiple cartilage-capped bone tumors growing outward from the metaphyses of long tubular bones. MO is genetically heterogeneous, and is associated with mutations in Exostosin-1 (EXT1) or Exostosin-2 (EXT2), both tumor-suppressor genes of the EXT gene family. All members of this multigene family encode glycosyltransferases involved in the adhesion and/or polymerization of heparin sulfate (HS) chains at HS proteoglycans (HSPGs). HSPGs have been shown to play a role in the diffusion of Ihh, thereby regulating chondrocyte proliferation and differentiation. EXT1 is located at 8q24.11-q24.13, and comprises 11 exons, whereas the 16 exon EXT2 is located at 11p12-p11. To date, an EXT1 or EXT2 mutation is detected in 70-95% of affected individuals. EXT1 mutations are detected in +/-65% of cases, versus +/-35% EXT2 mutations in MO patient cohorts. Inactivating mutations (nonsense, frame shift, and splice-site mutations) represent the majority of MO causing mutations (75-80%). In this article, the clinical aspects and molecular genetics of EXT1 and EXT2 are reviewed together with 895 variants in MO patients. An overview of the reported variants is provided by the online Multiple Osteochondromas Mutation Database (http://medgen.ua.ac.be/LOVD).

[Double mutant alleles in the EXT1 gene not previously reported in a teenager with hereditary multiple exostoses]. / Alelo doble mutante en el gen EXT1 no informado previamente en una adolescente con exostosis múltiple hereditaria.

Hereditary forms of multiple exostoses, now called EXT1/EXT2-CDG within Congenital Disorders of Glycosylation, are the most common benign bone tumors in humans and clinical description consists of the formation of several cartilage-capped bone tumors, usually benign and localized in the juxta-epiphyseal region of long bones, although wide body dissemination in severe cases is not uncommon. Onset of the disease is variable ranging from 2-3 years up to 13-15 years with an estimated incidence ranging from 1/18,000 to 1/50,000 cases in European countries. We present a double mutant alleles in the EXT1 gene not previously reported in a teenager and her family with hereditary multiple exostoses.

Alelo doble mutante en el gen EXT1 no informado previamente en una adolescente con exostosis múltiple hereditaria / Double mutant alleles in the EXT1 gene not previously reported in a teenager with hereditary multiple exostoses

Las formas hereditarias de exostosis múltiple, actualmente denominada EXT1 / EXT2-CDG dentro de los desórdenes congénitos de la glicosilación, son los tumores óseos benignos más comunes y se caracterizan por la formación de lesiones óseas cubiertas de cartílago, localizadas en yuxtaposición a epífisis de huesos largos, aunque, en los casos graves, pueden presentar una amplia distribución. El inicio es variable desde los 2-3 años hasta los 13-15 y presenta una incidencia estimada que va de 1/18 000 a 1/50 000 casos en los países europeos. Se presenta el caso de un doble alelo mutante en el gen EXT1 no informado previamente en una adolescente y su familia con exostosis múltiple hereditaria.

Hereditary forms of multiple exostoses, now called EXT1/EXT2-CDG within Congenital Disorders of Glycosylation, are the most common benign bone tumors in humans and clinical description consists of the formation of several cartilage-capped bone tumors, usually benign and localized in the juxta-epiphyseal region of long bones, although wide body dissemination in severe cases is not uncommon. Onset of the Alelo doble mutante en el gen EXT1 no informado previamente en una adolescente con exostosis múltiple hereditariaDouble mutant alleles in the EXT1 gene not previously reported in a teenager with hereditary multiple exostosesdisease is variable ranging from 2-3 years up to 13-15 years with an estimated incidence ranging from 1/18 000 to 1/50 000 cases in European countries. We present a double mutant alleles in the EXT1 gene not previously reported in a teenager and her family with hereditary multiple exostoses