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.
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Acknowledgments
We want to thank Sr. Klara Duha OSF, Asrama Fa’omasi, Laverna, Gunungsitoli for their assistance when performing clinical examinations. The help of the family Gaho from Hilinamöza’ua and the family Duha from Bawödobara with sampling and Gert W. Widmann from Kempten with transporting the probes is highly appreciated. Nata’alui Duha, Fabius Ndruru, Hatima Farasi, Oktoberlina Telaumbanua and Arozanolo Gulö from the staff of the Museum Pusaka Nias did a great job in their administrative and secretarial support of the field research. We thank Elisabeth Kirst and Nina Dalibor for their technical assistance in the genetic analyses, and Takako Hayashi for her technical assistance in the quantitative analysis of GAGs. This work was supported in part by a Grant-in-aid for Challenging Exploratory Research 25670018 (to K. S.); by a Grant-in-aid for Young Scientists (B) 25860037 (to S. M.) from the Japan Society for the Promotion of Science, Japan; by the Drs. Hiroshi Irisawa and Aya Irisawa Memorial Research Grant from the Japan Heart Foundation (to S. M.); by the Research Institute of Meijo University (Tenkai) (to S. M.).
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P.N. is a founder, CEO, and shareholder of ATLAS Biolabs GmbH. ATLAS Biolabs GmbH is a service provider for genomic analyses.
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B. S. Budde and S. Mizumoto contributed equally to this work.
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Budde, B.S., Mizumoto, S., Kogawa, R. et al. Skeletal dysplasia in a consanguineous clan from the island of Nias/Indonesia is caused by a novel mutation in B3GAT3 . Hum Genet 134, 691–704 (2015). https://doi.org/10.1007/s00439-015-1549-2
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DOI: https://doi.org/10.1007/s00439-015-1549-2