The Functional Study Of Cenani-Lenz Syndactyly Syndrome Causative Gene LRP4 In Limb And Kidney Development

Cenani-Lenz syndactyly syndrome (CLS) is an autosomal recessive skeletal disorder that results in syndactyly of hands and foot,malformation of the distal limb including shortening of the ulna and radius with fusion, metacarpals disorganization and fusion,syndactyly of the phalangeal,commonly associated with kidney agenesis/hypoplasia.Recent studies have shown that CLS was caused by mutations in low density lipoprotein receptor related protein 4 (LRP4) gene, located in chromosome 11 and coding LRP4 protein,which belongs to the low density lipoprotein receptor (LDLR)family.LRP4 is highly conserved across vertebrate species playing important roles during embryogenesis and organgenesis, poticular in bone development. Studies have indicated that LRP4 is a receptor of WNT signaling that antagonists and regulates canonical WNT signaling pathway. LRP4 mutations can dysregulate WNT pathway.We have identified a consanguineous Jordanian family with one member affected by CLS. The proband presents with a consistent expression of the syndrome restricted to the limbs and kidney, including fusion and disorganization of metacarpal and phalangeal bones, radioulnar synostosis, and typical syndactyly and oligodactyly of hands and feet, right kidney hypoplasia as well as left kidney with hypertrophy. Genetic analysis of the whole family by PCR and sequencing the candidate gene LRP4 revealed a novel missense mutation c.1117C>T,which caused arginin 373 to tryptophan in LRP4 protein. Luciferase assay suggested the mutation which is located in extracellular domains of LRP4 within highly conserved regions may abolish its antagonistic effect on LRP6/LRP5-mediated activation of WNT signaling.Using zebrafish as animal model,lrp4-knockdown embryos partially phenocopies the human disorder. The medial fin appeared blister as well as glomerulus and nephric tubule malformations.Our findings demonstrate LRP4 plays a critical role in distal limb and kidney development during vertebrate embryogenesis, provide important evidence for building the molecular network for limb and kidney development where LRP4 is considered as a key factor and assist in overcoming these diseases efficiently.