Defective splicing of Megf7/Lrp4, a regulator of distal limb development, in autosomal recessive mulefoot disease

Eric B. Johnson, David J. Steffen, Kristen W. Lynch, Joachim Herz

Research output: Contribution to journalArticle

35 Citations (Scopus)

Abstract

Mulefoot disease (MFD) is an autosomal recessive disorder of phenotypically variable expression that causes syndactyly in certain strains of cows. MFD maps to a narrow interval on bovine chromosome 15 that is syntenic to human chromosome 11p12-p11.2. This region contains MEGF7/LRP4 (approved gene symbol LRP4), a gene that encodes a member of the multifunctional low-density lipoprotein receptor gene family. Targeted and naturally occurring mutations in the murine Megf7/Lrp4 gene, a putative coreceptor in the Wnt signaling pathway, cause polysyndactyly in the rodent. Thus, Megf7/Lrp4 is a strong candidate for the MFD mutation. Using PCR analysis of tissue samples and sperm from confirmed homozygous MFD carriers, we have identified a functional single base pair mutation in the affected animals. We show that a G → A transition at the first nucleotide in the splice donor site of intron 37 completely disables this splice site. The abnormal splicing that is caused by this mutation predicts the generation of a dysfunctional membrane-anchored receptor lacking the normal cytoplasmic domain. These findings confirm that autosomal recessive loss-of-function mutations in Megf7/Lrp4 result in phenotypically similar forms of syndactyly in different mammalian species and that such mutations are the cause of MFD in bovines.

Original languageEnglish (US)
Pages (from-to)600-609
Number of pages10
JournalGenomics
Volume88
Issue number5
DOIs
StatePublished - Nov 2006

Fingerprint

Extremities
Syndactyly
Mutation
Genes
Cattle Diseases
Chromosomes, Human, Pair 15
RNA Splice Sites
Wnt Signaling Pathway
LDL Receptors
Human Chromosomes
Base Pairing
Introns
Spermatozoa
Rodentia
Nucleotides
Polymerase Chain Reaction
Membranes

Keywords

  • Apical ectodermal ridge
  • LDL receptor family
  • Lipoprotein receptor
  • Syndactyly
  • Wnt

ASJC Scopus subject areas

  • Genetics

Cite this

Defective splicing of Megf7/Lrp4, a regulator of distal limb development, in autosomal recessive mulefoot disease. / Johnson, Eric B.; Steffen, David J.; Lynch, Kristen W.; Herz, Joachim.

In: Genomics, Vol. 88, No. 5, 11.2006, p. 600-609.

Research output: Contribution to journalArticle

Johnson, Eric B. ; Steffen, David J. ; Lynch, Kristen W. ; Herz, Joachim. / Defective splicing of Megf7/Lrp4, a regulator of distal limb development, in autosomal recessive mulefoot disease. In: Genomics. 2006 ; Vol. 88, No. 5. pp. 600-609.
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