A Brazilian case arising from a homozygous canonical splice site <scp><i>SLC35A3</i></scp> variant leading to an in‐frame deletion

Miyake, Noriko; Stephan, Bruno de Oliveira; Kim, Chong; Matsumoto, Naomichi

doi:10.1111/cge.13909

Cited by 2 publications

(2 citation statements)

References 3 publications

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“…SLC35A3 encodes UDP-GlcNAc transporter, which incorporates UDP-GlcNAc into the Golgi apparatus from the cytosol (Figure 1; Ishida et al, 1999;Szulc et al, 2020). Compound heterozygous and homozygous mutations of SLC35A31 cause neuroskeletal disorder, which is characterized by arthrogryposis, knee and hip dislocations, anomalous vertebrae, hypotonia, autism, epilepsy, seizure, and mild to moderate intellectual disability (Table 5; Edvardson et al, 2013;Edmondson et al, 2017;Miyake et al, 2021). Moreover, the probands showed deficiency of several N-glycans, no difference in the biosynthesis of keratan sulfate, and hallmarks such as cleft palate, micrognathia, a patent foramen ovale, patent ductus arteriosus, posterior embryotoxon, short limbs, camptodactyly, talipes valgus, rocker-bottom feet, and facial dysmorphism (Edvardson et al, 2013;Edmondson et al, 2017).…”

Section: Arthrogryposis Intellectual Disability and Seizures Caused By Mutations In Slc35a3mentioning

confidence: 99%

Congenital Disorders of Deficiency in Glycosaminoglycan Biosynthesis

Mizumoto

Yamada

2021

Front. Genet.

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Glycosaminoglycans (GAGs) including chondroitin sulfate, dermatan sulfate, and heparan sulfate are covalently attached to specific core proteins to form proteoglycans, which are distributed at the cell surface as well as in the extracellular matrix. Proteoglycans and GAGs have been demonstrated to exhibit a variety of physiological functions such as construction of the extracellular matrix, tissue development, and cell signaling through interactions with extracellular matrix components, morphogens, cytokines, and growth factors. Not only connective tissue disorders including skeletal dysplasia, chondrodysplasia, multiple exostoses, and Ehlers-Danlos syndrome, but also heart and kidney defects, immune deficiencies, and neurological abnormalities have been shown to be caused by defects in GAGs as well as core proteins of proteoglycans. These findings indicate that GAGs and proteoglycans are essential for human development in major organs. The glycobiological aspects of congenital disorders caused by defects in GAG-biosynthetic enzymes including specific glysocyltransferases, epimerases, and sulfotransferases, in addition to core proteins of proteoglycans will be comprehensively discussed based on the literature to date.

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Section: Arthrogryposis Intellectual Disability and Seizures Caused By Mutations In Slc35a3mentioning

confidence: 99%

Congenital Disorders of Deficiency in Glycosaminoglycan Biosynthesis

Mizumoto

Yamada

2021

Front. Genet.

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“…A missense mutation (p.Val180Phe) in bovine SLC35A3 causes CVM. In humans, compound heterozygous mutations in SLC35A3 were identified in patients from three unrelated families with arthrogryposis, mental retardation, and seizures (AMRS; MIM 615553) [11][12][13]. Furthermore, a homozygous missense mutation in SLC35A3 was identified in a patient with severe vertebral anomalies [14].…”

Section: Introductionmentioning

confidence: 99%

Mice lacking nucleotide sugar transporter SLC35A3 exhibit lethal chondrodysplasia with vertebral anomalies and impaired glycosaminoglycan biosynthesis

et al. 2023

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SLC35A3 is considered an uridine diphosphate N-acetylglucosamine (UDP-GlcNAc) transporter in mammals and regulates the branching of N-glycans. A missense mutation in SLC35A3 causes complex vertebral malformation (CVM) in cattle. However, the biological functions of SLC35A3 have not been fully clarified. To address these issues, we have established Slc35a3–/–mice using CRISPR/Cas9 genome editing system. The generated mutant mice were perinatal lethal and exhibited chondrodysplasia recapitulating CVM-like vertebral anomalies. During embryogenesis, Slc35a3 mRNA was expressed in the presomitic mesoderm of wild-type mice, suggesting that SLC35A3 transports UDP-GlcNAc used for the sugar modification that is essential for somite formation. In the growth plate cartilage of Slc35a3–/–embryos, extracellular space was drastically reduced, and many flat proliferative chondrocytes were reshaped. Proliferation, apoptosis and differentiation were not affected in the chondrocytes of Slc35a3–/–mice, suggesting that the chondrodysplasia phenotypes were mainly caused by the abnormal extracellular matrix quality. Because these histological abnormalities were similar to those observed in several mutant mice accompanying the impaired glycosaminoglycan (GAG) biosynthesis, GAG levels were measured in the spine and limbs of Slc35a3–/–mice using disaccharide composition analysis. Compared with control mice, the amounts of heparan sulfate, keratan sulfate, and chondroitin sulfate/dermatan sulfate, were significantly decreased in Slc35a3–/–mice. These findings suggest that SLC35A3 regulates GAG biosynthesis and the chondrodysplasia phenotypes were partially caused by the decreased GAG synthesis. Hence, Slc35a3−/− mice would be a useful model for investigating the in vivo roles of SLC35A3 and the pathological mechanisms of SLC35A3-associated diseases.

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A Brazilian case arising from a homozygous canonical splice site SLC35A3 variant leading to an in‐frame deletion

Cited by 2 publications

References 3 publications

Congenital Disorders of Deficiency in Glycosaminoglycan Biosynthesis

Congenital Disorders of Deficiency in Glycosaminoglycan Biosynthesis

Mice lacking nucleotide sugar transporter SLC35A3 exhibit lethal chondrodysplasia with vertebral anomalies and impaired glycosaminoglycan biosynthesis

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