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Gene Regulation in Van Buchem Disease

  • Gabriela G. LootsEmail author
Chapter

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.

Keywords

High bone mass Osteopetrosis SOST Sclerostin Van Buchem disease Sclerosteosis Van Buchem deletion ECR5 enhancer 

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

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Copyright information

© Springer Science+Business Media, LLC 2012

Authors and Affiliations

  1. 1.Biology and Biotechnology DivisionLawrence Livermore National LaboratoryLivermoreUSA
  2. 2.School of Natural SciencesUniversity of California MercedMercedUSA

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