Homozygous <i>CHST11</i> mutation in chondrodysplasia, brachydactyly, overriding digits, clino-symphalangism and synpolydactyly

Shabbir, Rana Muhammad Kamran; Nalbant, Gökhan; Ahmad, Nafees; Malik, Sajid; Tolun, Aslıhan

doi:10.1136/jmedgenet-2017-105003

Cited by 13 publications

(9 citation statements)

References 24 publications

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“…These results reproducibly demonstrate that genetic mutations in genes required for PG biosynthesis in mice result in reduced skeletal growth or long bone dysplasia resembling human patients with skeletal disorders caused by recessive mutations in these genes. ( 76–80 )…”

Section: Resultsmentioning

confidence: 99%

Germline Saturation Mutagenesis Induces Skeletal Phenotypes in Mice

Rios

Denton

Russell

et al. 2020

Journal of Bone and Mineral Research

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Proper embryonic and postnatal skeletal development require coordination of myriad complex molecular mechanisms. Disruption of these processes, through genetic mutation, contributes to variation in skeletal development. We developed a high‐throughput N‐ethyl‐N‐nitrosourea (ENU)‐induced saturation mutagenesis skeletal screening approach in mice to identify genes required for proper skeletal development. Here, we report initial results from live‐animal X‐ray and dual‐energy X‐ray absorptiometry (DXA) imaging of 27,607 G3 mice from 806 pedigrees, testing the effects of 32,198 coding/splicing mutations in 13,020 genes. A total of 39.7% of all autosomal genes were severely damaged or destroyed by mutations tested twice or more in the homozygous state. Results from our study demonstrate the feasibility of in vivo mutagenesis to identify mouse models of skeletal disease. Furthermore, our study demonstrates how ENU mutagenesis provides opportunities to create and characterize putative hypomorphic mutations in developmentally essential genes. Finally, we present a viable mouse model and case report of recessive skeletal disease caused by mutations in FAM20B. Results from this study, including engineered mouse models, are made publicly available via the online Mutagenetix database. © 2021 American Society for Bone and Mineral Research (ASBMR).

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Section: Resultsmentioning

confidence: 99%

Germline Saturation Mutagenesis Induces Skeletal Phenotypes in Mice

Rios

Denton

Russell

et al. 2020

Journal of Bone and Mineral Research

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“…Moreover, scoliosis, dislocated patellae and fibulae, pectus excavatum and mild osteoarthritis have been reported. In this family a deletion in the CHST11 gene encoding for carbohydrate sulfotransferase 11 has been detected [90]. The enzyme also known as chondroitin-4-sulfotrasferase 1 (C4ST1) is a Golgi sulfotransferase responsible for sulfate transfer to C4 of the GalNAc residues in CS chain.…”

Section: Skeletal Dysplasias Linked To Proteins Involved In Gag Sulfamentioning

confidence: 99%

Skeletal Dysplasias Caused by Sulfation Defects

Paganini

Tota

Superti‐Furga

et al. 2020

IJMS

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Proteoglycans (PGs) are macromolecules present on the cell surface and in the extracellular matrix that confer specific mechanical, biochemical, and physical properties to tissues. Sulfate groups present on glycosaminoglycans, linear polysaccharide chains attached to PG core proteins, are fundamental for correct PG functions. Indeed, through the negative charge of sulfate groups, PGs interact with extracellular matrix molecules and bind growth factors regulating tissue structure and cell behavior. The maintenance of correct sulfate metabolism is important in tissue development and function, particularly in cartilage where PGs are fundamental and abundant components of the extracellular matrix. In chondrocytes, the main sulfate source is the extracellular space, then sulfate is taken up and activated in the cytosol to the universal sulfate donor to be used in sulfotransferase reactions. Alteration in each step of sulfate metabolism can affect macromolecular sulfation, leading to the onset of diseases that affect mainly cartilage and bone. This review presents a panoramic view of skeletal dysplasias caused by mutations in genes encoding for transporters or enzymes involved in macromolecular sulfation. Future research in this field will contribute to the understanding of the disease pathogenesis, allowing the development of targeted therapies aimed at alleviating, preventing, or modifying the disease progression.

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“…Osteochondrodysplasia, Brachydactyly, and Overlapping Malformed Digits Caused by Mutations in CHST11 CHST11 encodes chondroitin 4-O-sulfotransferase 1 (C4ST1), which transfers a sulfate group from PAPS to the C-4 hydroxy group of GalNAc residues in CS chains (Figure 3; Hiraoka et al, 2000;Yamauchi et al, 2000). Homozygous in-frame deletion of 15 nucleotides in CHST11, which results in the deletion of amino acids (Lys156-Asn160), causes limb malformations including brachydactyly, overriding digits, clino-symphalangism, syndactyly, and hexadactyly, and skeletal defects including scoliosis, dislocation of patellae and fibulae, and pectus excavatum (Table 2; Shabbir et al, 2018). Biochemical analyses using a recombinant enzyme as well as patients' cells have not been conducted to our knowledge.…”

Section: Spondyloepiphyseal Dysplasia With Congenital Joint Dislocations Larsen Syndrome and Humero-spinal Dysostosis Caused By Mutationsmentioning

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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Homozygous CHST11 mutation in chondrodysplasia, brachydactyly, overriding digits, clino-symphalangism and synpolydactyly

Cited by 13 publications

References 24 publications

Germline Saturation Mutagenesis Induces Skeletal Phenotypes in Mice

Germline Saturation Mutagenesis Induces Skeletal Phenotypes in Mice

Skeletal Dysplasias Caused by Sulfation Defects

Congenital Disorders of Deficiency in Glycosaminoglycan Biosynthesis

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