Cell
Volume 78, Issue 6, 23 September 1994, Pages 1073-1087
Journal home page for Cell

Article
The diastrophic dysplasia gene encodes a novel sulfate transporter: Positional cloning by fine-structure linkage disequilibrium mapping

https://doi.org/10.1016/0092-8674(94)90281-XGet rights and content

Abstract

Diastrophic dysplasia (DTD) is a well-characterized autosomal recessive osteochondrodysplasia with clinical features including dwarfism, spinal deformation, and specific joint abnormalities. The disease occurs in most populations, but is particularly prevalent in Finland owing to an apparent founder effect. DTD maps to distal chromosome 5q and, based on linkage disequilibrium studies in the Finnish population, we had previously predicted that the DTD gene should lie about 64 kb away from the CSF1R locus. Here, we report the positional cloning of the DTD gene by fine-structure linkage disequilibrium mapping. The gene lies in the predicted location, approximately 70 kb proximal to CSF1R, and encodes a novel sulfate transporter. Impaired function of its product is likely to lead to undersulfation of proteoglycans in cartilage matrix and thereby to cause the clinical phenotype of the disease. These results demonstrate the power of linkage disequilibrium mapping in isolated populations for positional cloning.

References (85)

  • J.M. Keller et al.

    Amino acid sulfur as a source of sulfate for sulfated proteoglycans produced by Swiss mouse 3T3 cell

    Biochim. Biophys. Acta

    (1987)
  • P. Klein et al.

    The detection and classification of membrane-spanning proteins

    Biochim. Biophys. Acta

    (1985)
  • K.R. Krijgsheld et al.

    An evaluation of methods to decrease the availability of inorganic sulfate for sulfate conjugation in the rat in vivo

    Biochem. Pharmacol.

    (1981)
  • K.R. Krijgsheld et al.

    The dependence of the rate of sulfate conjugation on the plasma concentration of inorganic sulfate in the rat in vivo

    Biochem. Pharmacol.

    (1982)
  • J. Kyte et al.

    A simple method for displaying the hydropathic character of a protein

    J. Mol. Biol.

    (1982)
  • X. Li et al.

    A YAC contig of approximately 3 Mb from human chromosome 5q31-q33

    Genomics

    (1994)
  • O.H. Lowry et al.

    Protein measurement with the folin phenol reagent

    J. Biol. Chem.

    (1951)
  • H. Lucke et al.

    Sulphate-sodium cotransport by brush-border membrane vesicles isolated from rat ileum

    Gastroenterology

    (1981)
  • J.P. Pennypacker et al.

    Brachymorphic mice (bm/bm): A generalized biochemical defect expressed primarily in cartilage

    Dev. Biol.

    (1981)
  • W.M. Roberts et al.

    Tandem linkage of human CSF-1 receptor (c-fms) and PDGF receptor genes

    Cell

    (1988)
  • E.G. Schneider et al.

    Sodium-dependent transport of inorganic sulfate by rabbit renal brush-border membrane vesicles

    J. Biol. Chem.

    (1984)
  • M. Sobue et al.

    Effect of environmental sulfate concentration on the synthesis of low and high sulfated chondroitin sulfates by chick embryo cartilage

    J. Biol. Chem.

    (1978)
  • K. Sugahara et al.

    Defect in 3′-phosphoadenosine 5′-phosphosulfate synthesis in brachymorphic mice - I

    Arch. Biochem. Biophys.

    (1982)
  • K. Sugahara et al.

    Defect in 3′-phosphoadenosine 5′-phosphosulfate synthesis in brachymorphic mice - II

    Arch. Biochem. Biophys.

    (1982)
  • P. von Dippe et al.

    Analysis of the transport system for inorganic anions in normal and transformed hepatocytes

    J. Biol. Chem.

    (1982)
  • I. Aksentijevich et al.

    Familial Mediterranean fever (FMF) in Moroccan Jews: demonstration of a founder effect by extended haplotype analysis

    Am. J. Hum. Genet.

    (1993)
  • A.I. Cabantchik et al.

    The anion transport system of the red blood cell: the role of membrane protein evaluated by the use of “probes”

    Biochim. Biophys. Acta

    (1978)
  • F. Cavalcanti et al.

    Friedreich's disease: a linkage study in southern and central Italy

    Acta. Neurol. (Napoli)

    (1992)
  • A. de la Chapelle

    Disease gene mapping in isolated human populations: the example of Finland

    J. Med. Genet.

    (1993)
  • B.J. de Vries et al.

    The effect of salicylate on anatomically intact articular cartilage is influenced by sulfate and serum in the culture medium

    J. Rheumatol.

    (1986)
  • S. Dear et al.

    A sequence assembly and editing program for efficient management of large projects

    Nucl. Acids Res.

    (1991)
  • M. Diab et al.

    Abnormality of type IX collagen in a patient with diastrophic dysplasia

    Am. J. Med. Genet.

    (1994)
  • V.C. Duance et al.

    Type IX collagen function in hyaline cartilage

    Ann. NY Acad. Sci.

    (1990)
  • A. Elgavish et al.

    Sulfation by human lung fibroblasts: SO4−2 and sulfur-containing amino acids as sources for macromolecular sulfation

    Am. Phys. Soc.

    (1991)
  • A. Elgavish et al.

    Sulfate transport in human lung fibroblasts (IMR-90)

    J. Cell. Physiol.

    (1985)
  • D.M. Engelman et al.

    Identifying nonpolar transbilayer helices in amino acid sequences of membrane proteins

    Annu. Rev. Biophys. Chem.

    (1986)
  • J.A. Estep et al.

    Kinetics of sulfated mucous glycoprotein-secretion in dog trachea in vitro

    J. Appl. Physiol.

    (1981)
  • S.P. Feschenko et al.

    Molecular heterogeneity of proteoglycan aggregates of human hyalin cartilage in normal conditions and in systematic bone dysplasia

    Vopr. Med. Khim.

    (1989)
  • R.M. Gardiner

    Genetic analysis of Batten disease

    J. Inherit. Metab. Dis.

    (1993)
  • B.A. Hamilton et al.

    Rapid isolation of long cDNA clones from existing libraries

    Nucl. Acids Res.

    (1991)
  • A. Hampe et al.

    Nucleotide sequence and structural organization of the human FMS proto-oncogene

    Oncogene Res.

    (1989)
  • J. Hästbacka et al.

    Diastrophic dysplasia gene maps to the distal long arm of chromosome 5

  • Cited by (0)

    View full text