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Mutations in orthologous genes in human spondyloepimetaphyseal dysplasia and the brachymorphic mouse

Nature Genetics volume 20, pages 157–162 (1998)Cite this article

Abstract

The osteochondrodysplasias are a genetically heterogeneous group of disorders affecting skeletal development, linear growth and the maintenance of cartilage and bone. We have studied a large inbred Pakistani family with a distinct form of recessively inherited spondyloepimetaphyseal dysplasia (SEMD) and mapped a gene associated with this dwarfing condition to chromosome 10q23–24, a region syntenic with the locus for the brachymorphic mutation on mouse chromosome 19. We identified two orthologous genes, ATPSK2 and Atpsk2, encoding novel ATP sulfurylase/APS kinase orthologues in the respective regions of the human and mouse genomes. We characterized a nonsense mutation in ATPSK2 in the SEMD family and a missense mutation in the region of Atpsk2 encoding the APS kinase activity in the brachymorphic mouse. ATP sulfurylase/APS kinase catalyses the metabolic activation of inorganic sulfate to PAPS, the universal donor for post-translational protein sulfation in all cell types. The cartilage-specificity of the human and mouse phenotypes provides further evidence of the critical role of sulfate activation in the maturation of cartilage extracellular matrix molecules and the effect of defects in this process on the architecture of cartilage and skeletogenesis.

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Figure 1: Partial pedigree of the Pakistani SEMD family showing the most likely haplotypes for the chromosome 10 markers.
Figure 2: Genetic mapping of SEMD Pakistani type and brachymorphic.
Figure 3: ATPSK2 mutation in the SEMD family.
Figure 4: Alignment of the segment of the mouse Atpsk2 encoded protein containing the brachymorphic mutation with similar regions from orthologous and related proteins from other species.

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Acknowledgements

This study was supported in part by NIH grants HD22657 (D.H.C.), AR02038 (D.K.), HL51480 (R.T.S.) and HL31698 (R.T.S.), by award C-QU/BIO(264) from the Pakistan Science Foundation (M.A. and M.F.U.) and by grant 45401.95 from the Swiss National Science Foundation (A.S.-F.). We thank E. Delot-Vilain for assistance with the preparation of figures and S. Brodie and E. Delot-Vilain for helpful discussions during the course of this work. We thank A. Christiano and J.A. McGrath for providing reference DNA samples from individuals of Pakistani origin.

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Authors and Affiliations

  1. Ahmanson Department of Pediatrics, Steven Spielberg Pediatric Research Center, Los Angeles, 90048, California, USA

    Muhammad Faiyaz ul Haque, Lily M. King, Deborah Krakow, Rita M. Cantor & Daniel H. Cohn

  2. Department of Obstetrics and Gynecology, Cedars-Sinai Research Institute, Los Angeles, 90048, California, USA

    Deborah Krakow

  3. Molecular and Cellular Biology Department, Roswell Park Cancer Institute, Buffalo, 14263 , New York, USA

    Michael E. Rusiniak & Richard T. Swank

  4. Division of Metabolic and Molecular Diseases, Department of Pediatrics, University Children's Hospital, Zurich, CH-8032, Switzerland

    Andrea Superti-Furga

  5. Department of Biological Sciences, Quaid-i-Azam University, Islamabad, Pakistan

    Muhammad Faiyaz ul Haque, Sayedul Haque, Hasan Abbas & Mahmud Ahmad

  6. Department of Dermatology, Columbia University College of Physicians and Surgeons, New York, 10032, New York, USA

    Wasim Ahmad

  7. Department of Pediatrics, UCLA School of Medicine, Los Angeles, California, USA

    Daniel H. Cohn

  8. Department of Obstetrics and Gynecology, UCLA School of Medicine, Los Angeles, California, USA

    Deborah Krakow

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  1. Muhammad Faiyaz ul Haque
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Correspondence to Daniel H. Cohn.

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Haque, M., King, L., Krakow, D. et al. Mutations in orthologous genes in human spondyloepimetaphyseal dysplasia and the brachymorphic mouse. Nat Genet 20, 157–162 (1998). https://doi.org/10.1038/2458

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