Congenital syndactyly in cattle: four novel mutations in the low density lipoprotein receptor-related protein 4 gene (LRP4)

Abstract

BackgroundIsolated syndactyly in cattle, also known as mulefoot, is inherited as an autosomal recessive trait with variable penetrance in different cattle breeds. Recently, two independent mutations in the bovine LRP4 gene have been reported as the primary cause of syndactyly in the Holstein and Angus cattle breeds.ResultsWe confirmed the previously described LRP4 exon 33 two nucleotide substitution in most of the affected Holstein calves and revealed additional evidence for allelic heterogeneity by the identification of four new LRP4 non-synonymous point mutations co-segregating in Holstein, German Simmental and Simmental-Charolais families.ConclusionWe confirmed a significant role of LRP4 mutations in the pathogenesis of congenital syndactyly in cattle. The newly detected missense mutations in the LRP4 gene represent independent mutations affecting different conserved protein domains. However, the four newly described LRP4 mutations do still not explain all analyzed cases of syndactyly.

Lrp4 Is a Receptor for Agrin and Forms a Complex with MuSK

“…Mutations in lrp4 , which truncate Lrp4 and lead to a loss of the cytoplasmic domain without disruption of the ectodomain, cause syndactyly without apparent defects in neuromuscular synapses (Drogemuller et al, 2007; Johnson et al, 2005). Our findings show that the cytoplasmic domain of Lrp4 is dispensable for Agrin-responsiveness.…”

ApoE, ApoE Receptors, and the Synapse in Alzheimer's Disease

“…Agrin is released from the motor neuron and signals through APP, MuSK and Lrp4 to recruit nicotinic acetylcholine receptors (AChRs). Importantly, the absolute requirement of Lrp4 for NMJ development in mice, but intriguingly not in humans [86] and cattle [91], means that mice that are completely deficient in Lrp4 die perinatally, which has precluded effective study of the role of Lrp4 in the CNS until recently [92]. A recent study used a mouse model in which Lrp4 is expressed in the muscle on an Lrp4 knockout background, permitting survival into adulthood.…”

Lipoprotein receptors – an evolutionarily ancient multifunctional receptor family

“…LRP4 suppresses Wnt signaling, probably by competing for LRP5/6 in the Wnt/Fz signaling complex at the membrane level and through its ligand binding domain by altering the effect of extracellular ligands (Figure 2D (Dietrich et al 2010; Johnson et al 2005; Weatherbee et al 2006)). LRP4 knockout mice present with several remarkable phenotypes, including defects of kidney development (Karner et al 2010; Li et al 2010; Weatherbee et al 2006), limb development (Drogemuller et al 2007; Duchesne et al 2006; Johnson et al 2005; Simon-Chazottes et al 2006; Weatherbee et al 2006), tooth development (Johnson et al 2005) and failure to form neuromuscular junctions (Weatherbee et al 2006). Not all of these defects can be explained by deregulation of Wnt signaling alone, suggesting that LRP4 is also involved in the execution or modulation of other signaling pathways.…”