Defective splicing of Megf7/Lrp4, a regulator of distal limb development, in autosomal recessive mulefoot disease
Open accessAbstract
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.
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Lrp4 is the gene mutated in Cenani-Lenz syndrome.
“Lrp4 is more commonly known as the gene defective in Cenani-Lenz syndrome [83–86]”
From ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease (2017) · cites this paper as [85]
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- Authors
- Johnson, E. B., Steffen, D. J., Lynch, K. W., & Herz, J.
- Affiliations
- The University of Texas Southwestern Medical Center (US)
- University of Nebraska–Lincoln (US)
- Corresponding author
- Herz, Joachim
- Venue
- Genomics
- Publisher
- Elsevier BV
- Published
- 2006-11
- Volume
- 88
- Issue
- 5
- Pages
- 600-609
- ISSN
- 0888-7543 (ISSN-L)
- OpenAlex
- W2113505118
- Cited by
- 62
- References
- 36
- Citations by year
- 2026: 2 · 2025: 5 · 2024: 2 · 2023: 1 · 2022: 4 · 2021: 5 · 2020: 2 · 2019: 2 · 2018: 1 · 2017: 5 · 2016: 1 · 2015: 3 · 2014: 3 · 2013: 4 · 2012: 3
- FWCI
- 3.14
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Licence
- Locations
- Genomics (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Alexander von Humboldt-Stiftung
- Ministry of Food and Drug Safety
- National Institutes of Health
- National Heart, Lung, and Blood Institute (HL-20948, HL63762, R37HL063762, P01HL020948)
- National Institute of Neurological Disorders and Stroke (NS43408, R01NS043408)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Developmental Biology › Congenital limb and hand anomalies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic and phenotypic traits in livestock
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Developmental Biology and Gene Regulation
- Keywords
- LRP4, splice site mutation, aberrant splicing, syndactyly, autosomal recessive inheritance, low-density lipoprotein receptor family, Wnt signaling, loss-of-function mutations
- MeSH terms
- Amino Acid Sequence, Animals, Base Sequence, Cattle, Cattle Diseases, Chromosome Mapping, DNA, Extremities, Genes, Recessive, Humans, Introns, Molecular Sequence Data, Receptors, LDL, RNA Splicing, Syndactyly, Two-Hybrid System Techniques, Genomics, LDL-Receptor Related Proteins, Mice
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