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Gene Regulation in Van Buchem Disease

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Gene Regulatory Sequences and Human Disease

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Abstract

Van Buchem disease (VB) is a rare autosomal recessive disorder in which progressive bone overgrowth leads to very dense bones, distortion of the face, and entrapment of cranial nerves. It uniquely stands out as a congenital disorder likely to be caused by noncoding mutations for several reasons: (1) it maps to the same locus on human chromosome 17q12–21 as a highly similar disorder, sclerosteosis; (2) several single specific mutations have been identified in sclerosteosis patients that all predict null alleles in the determinant gene, sclerostin or SOST; (3) no coding mutations in SOST have been identified in VB patients; and (4) all VB patients carry a homozygous 52-kb noncoding deletion downstream of the SOST transcript. Here, we describe how by using comparative sequence analysis, BAC recombination, and enhancer assays, in combination with the generation of transgenic and knockout mice, it has been shown that human SOST is essential for maintaining healthy bone metabolism and that VB disease is caused by a noncoding deletion that removes a SOST-specific regulatory element, ECR5.

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Abbreviations

BAC:

Bacterial artificial chromosome

BMD:

Bone mineral density

bp:

Base pair

chr:

Chromosome

cm:

Centimeter

cM:

Centimorgan

ECR:

Evolutionary conserved region

GFP:

Green fluorescent protein

HBM:

High bone mass

Hsp68:

Heat shock protein 68

Kb:

Kilobase

KO:

Knockout

lacZ:

Beta-galactosidase

lb:

Pound

LOD:

Logarithm (base 10) of odds

Mb:

Megabase

MEF2:

Myocyte enhancer factor 2

microCT:

Micro-computed tomography

mut:

Mutation

NDP:

Norrie disease protein

PCR:

Polymerase chain reaction

PRDC:

Protein related to dan and cerberus

PTH:

Parathyroid hormone

qPCR:

Quantitative polymerase chain reaction

rtPCR:

Reverse transcriptase polymerase chain reaction

SNP:

Single nucleotide polymorphism

SOST:

Sclerostin

SV40:

Simian vacuolating virus 40

TFBS:

Transcription factor binding site

TGF-β:

Transforming growth factor beta

VB:

Van Buchem disease

VBΔ:

Van Buchem deletion

WT:

Wild type

References

  • Arnold MA et al (2007) MEF2C transcription factor controls chondrocyte hypertrophy and bone development. Dev Cell 12(3):377–389

    Article  PubMed  CAS  Google Scholar 

  • Balemans W et al (1999) Localization of the gene for sclerosteosis to the van Buchem disease-gene region on chromosome 17q12–q21. Am J Hum Genet 64(6):1661–1669

    Article  PubMed  CAS  Google Scholar 

  • Balemans W et al (2001) Increased bone density in sclerosteosis is due to the deficiency of a novel secreted protein (SOST). Hum Mol Genet 10(5):537–543

    Article  PubMed  CAS  Google Scholar 

  • Balemans W et al (2002) Identification of a 52 kb deletion downstream of the SOST gene in patients with van Buchem disease. J Med Genet 39(2):91–97

    Article  PubMed  CAS  Google Scholar 

  • Beighton P et al (1984) The syndromic status of sclerosteosis and van Buchem disease. Clin Genet 25(2):175–181

    Article  PubMed  CAS  Google Scholar 

  • Brunkow ME et al (2001) Bone dysplasia sclerosteosis results from loss of the SOST gene product, a novel cystine knot-containing protein. Am J Hum Genet 68(3):577–589

    Article  PubMed  CAS  Google Scholar 

  • Hamersma H, Gardner J, Beighton P (2003) The natural history of sclerosteosis. Clin Genet 63(3):192–197

    Article  PubMed  CAS  Google Scholar 

  • Janssens K, Van Hul W (2002) Molecular genetics of too much bone. Hum Mol Genet 11(20):2385–2393

    Article  PubMed  CAS  Google Scholar 

  • Keller H, Kneissel M (2005) SOST is a target gene for PTH in bone. Bone 37(2):148–158

    Article  PubMed  CAS  Google Scholar 

  • Kornak U, Mundlos S (2003) Genetic disorders of the skeleton: a developmental approach. Am J Hum Genet 73(3):447–474

    Article  PubMed  CAS  Google Scholar 

  • Kraenzlin ME, Meier C (2011) Parathyroid hormone analogues in the treatment of osteoporosis. Nat Rev Endocrinol 7(11):647–656

    Article  PubMed  CAS  Google Scholar 

  • Lee EC et al (2001) A highly efficient Escherichia coli-based chromosome engineering system adapted for recombinogenic targeting and subcloning of BAC DNA. Genomics 73(1):56–65

    Article  PubMed  CAS  Google Scholar 

  • Leupin O et al (2007) Control of the SOST bone enhancer by PTH using MEF2 transcription factors. J Bone Miner Res 22(12):1957–1967

    Article  PubMed  CAS  Google Scholar 

  • Li X et al (2008) Targeted deletion of the sclerostin gene in mice results in increased bone formation and bone strength. J Bone Miner Res 23(6):860–869

    Article  PubMed  Google Scholar 

  • Lin Q et al (1998) Requirement of the MADS-box transcription factor MEF2C for vascular development. Development 125(22):4565–4574

    PubMed  CAS  Google Scholar 

  • Loots GG et al (2000) Identification of a coordinate regulator of interleukins 4, 13, and 5 by cross-species sequence comparisons. Science 288(5463):136–140

    Article  PubMed  CAS  Google Scholar 

  • Loots GG et al (2005) Genomic deletion of a long-range bone enhancer misregulates sclerostin in Van Buchem disease. Genome Res 15(7):928–935

    Article  PubMed  CAS  Google Scholar 

  • Nobrega MA et al (2003) Scanning human gene deserts for long-range enhancers. Science 302(5644):413

    Article  PubMed  CAS  Google Scholar 

  • Potthoff MJ et al (2007) Regulation of skeletal muscle sarcomere integrity and postnatal muscle function by Mef2c. Mol Cell Biol 27(23):8143–8151

    Article  PubMed  CAS  Google Scholar 

  • Staehling-Hampton K et al (2002) A 52-kb deletion in the SOST-MEOX1 intergenic region on 17q12–q21 is associated with van Buchem disease in the Dutch population. Am J Med Genet 110(2):144–152

    Article  PubMed  Google Scholar 

  • Uitterlinden AG et al (2004) Polymorphisms in the sclerosteosis/van Buchem disease gene (SOST) region are associated with bone-mineral density in elderly whites. Am J Hum Genet 75(6):1032–1045

    Article  PubMed  CAS  Google Scholar 

  • Van Buchem FS, Hadders HN, Ubbens R (1955) An uncommon familial systemic disease of the skeleton: hyperostosis corticalis generalisata familiaris. Acta Radiol 44(2):109–120

    Article  Google Scholar 

  • Van Hul W et al (1998) Van Buchem disease (hyperostosis corticalis generalisata) maps to chromosome 17q12–q21. Am J Hum Genet 62(2):391–399

    Article  PubMed  Google Scholar 

  • Van Hul W et al (2001) Molecular and radiological diagnosis of sclerosing bone dysplasias. Eur J Radiol 40(3):198–207

    Article  PubMed  Google Scholar 

  • Wang DZ et al (2001) The Mef2c gene is a direct transcriptional target of myogenic bHLH and MEF2 proteins during skeletal muscle development. Development 128(22):4623–4633

    PubMed  CAS  Google Scholar 

  • Winkler DG et al (2003) Osteocyte control of bone formation via sclerostin, a novel BMP antagonist. EMBO J 22(23):6267–6276

    Article  PubMed  CAS  Google Scholar 

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Author information

Authors and Affiliations

  1. Biology and Biotechnology Division, Lawrence Livermore National Laboratory, 7000 East Avenue, L-452, Livermore, CA, 94550, USA

    Gabriela G. Loots

  2. School of Natural Sciences, University of California Merced, Merced, CA, 95343, USA

    Gabriela G. Loots

Authors
  1. Gabriela G. Loots
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Correspondence to Gabriela G. Loots .

Editor information

Editors and Affiliations

  1. Institute for Human Genetics, 513 Parnassus Ave., San Francisco, 94143, USA

    Nadav Ahituv

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Loots, G.G. (2012). Gene Regulation in Van Buchem Disease. In: Ahituv, N. (eds) Gene Regulatory Sequences and Human Disease. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-1683-8_4

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