title: Skeletal dysplasia in a consanguineous clan from the island of Nias/Indonesia is caused by a novel mutation in B3GAT3.
abstract: We describe a large family with disproportionate short stature and bone dysplasia from Nias in which we observed differences in severity when comparing the phenotypes of affected individuals from two remote branches. We conducted a linkage scan in the more severely affected family branch and determined a critical interval of 4.7 cM on chromosome 11. Sequencing of the primary candidate gene TBX10 did not reveal a disease-causing variant. When performing whole exome sequencing we noticed a homozygous missense variant in B3GAT3, c.419C>T [p.(Pro140Leu)]. B3GAT3 encodes β-1,3-glucuronyltransferase-I (GlcAT-I). GlcAT-I catalyzes an initial step of proteoglycan synthesis and the mutation p. (Pro140Leu) lies within the donor substrate-binding subdomain of the catalytic domain. In contrast to the previously published mutation in B3GAT3, c.830G>A [p.(Arg277Gln)], no heart phenotype could be detected in our family. Functional studies revealed a markedly reduced GlcAT-I activity in lymphoblastoid cells from patients when compared to matched controls. Moreover, relative numbers of glycosaminoglycan (GAG) side chains were decreased in patient cells. We found that Pro140Leu-mutant GlcAT-I cannot efficiently transfer GlcA to the linker region trisaccharide. This failure results in a partial deficiency of both chondroitin sulfate and heparan sulfate chains. Since the phenotype of the Nias patients differs from the Larsen-like syndrome described for patients with mutation p.(Arg277Gln), we suggest mutation B3GAT3:p.(Pro140Leu) to cause a different type of GAG linkeropathy showing no involvement of the heart.
authors.affiliation: Cologne Center for Genomics (CCG), University of Cologne, Cologne, Germany.
authors.forename: Birgit S
authors.initials: BS
authors.lastname: Budde
authors.forename: Shuji
authors.initials: S
authors.lastname: Mizumoto
authors.forename: Ryo
authors.initials: R
authors.lastname: Kogawa
authors.forename: Christian
authors.initials: C
authors.lastname: Becker
authors.forename: Janine
authors.initials: J
authors.lastname: Altmüller
authors.forename: Holger
authors.initials: H
authors.lastname: Thiele
authors.forename: Franz
authors.initials: F
authors.lastname: Rüschendorf
authors.forename: Mohammad R
authors.initials: MR
authors.lastname: Toliat
authors.forename: Gerrit
authors.initials: G
authors.lastname: Kaleschke
authors.forename: Johannes M
authors.initials: JM
authors.lastname: Hämmerle
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Höhne
authors.forename: Kazuyuki
authors.initials: K
authors.lastname: Sugahara
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Ingo
authors.initials: I
authors.lastname: Kennerknecht
mesh_terms: D000293:Adolescent; D000328:Adult; D019943:Amino Acid Substitution; D001848:Bone Diseases, Developmental / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D005260:Female; D030342:Genetic Diseases, Inborn / Q000201:enzymology / Q000235:genetics* / Q000473:pathology; D014453:Glucuronosyltransferase / Q000378:metabolism; D006801:Humans; D007223:Infant; D008297:Male; D020125:Mutation, Missense; D010375:Pedigree; D017434:Protein Structure, Tertiary
chemical_list: C000594393:B3GAT3 protein, human; D014453:Glucuronosyltransferase