LRP4 – Cenani-Lenz Syndactyly Syndrome

Low-density lipoprotein receptor–related protein 4 (LRP4) is a single-pass transmembrane coreceptor that antagonizes LRP5/6-mediated Wnt/β-catenin signaling during embryonic limb and kidney development. LRP4 binds sclerostin and other modulators to fine-tune canonical Wnt output in the limb bud. Autosomal recessive biallelic mutations in LRP4 underlie Cenani-Lenz syndactyly syndrome (Cenani-Lenz syndrome), a rare disorder marked by complete syndactyly, oligodactyly, radioulnar synostosis, and variable renal hypoplasia. Affected individuals typically present with osseous fusion of fingers and toes and characteristic facial features. Syndactyly is frequently accompanied by renal anomalies, illustrating the pleiotropic roles of Wnt signaling. Both human studies and animal models have solidified the pathogenic link between LRP4 loss-of-function and this skeletal dysplasia.

Discovery of the gene–disease relationship employed homozygosity mapping in 12 unrelated consanguineous families with autosomal-recessive CLS, identifying recessive LRP4 variants as causal (PMID:20381006). Sequencing revealed diverse allelic classes including missense c.3049T>C (p.Cys1017Arg), splice-site c.547+1G>A, and deep intronic changes that disrupt receptor trafficking and ligand binding. These variants segregated fully with disease in multi-affected families, encompassing >12 families and >20 probands. No unaffected homozygotes were observed, and carrier parents were clinically normal under a recessive model. The reproducibility across pedigrees and absence of benign homozygotes support a definitive association.

Subsequent case reports have expanded the variant spectrum, describing novel truncating mutations such as c.2498del (p.Thr833fs) and c.2830C>T (p.Gln944Ter) associated with severe prenatal lethal presentations (PMID:24924585), as well as rare missense alleles like c.4910G>A (p.Cys1637Tyr) in siblings with hypoglycaemia and radioulnar synostosis (PMID:31895055) and c.2858T>C (p.Leu953Pro) in a large Pakistani pedigree restricted to limb and kidney anomalies (PMID:23664847). Genotype–phenotype correlations indicate that early-truncating alleles yield more severe skeletal phenotypes, whereas hypomorphic variants present with milder limb involvement.

Functional studies provide mechanistic insight: LRP4 loss-of-function elevates Wnt/β-catenin signaling in the limb bud, leading to digit malformations. Lrp4-deficient mouse models exhibit polysyndactyly and phalangeal disorganization mirroring human CLS (PMID:16517118). In vitro, patient-derived missense and splice mutants show impaired sclerostin facilitation and inability to inhibit LRP6-mediated Wnt activation. Zebrafish lrp4 knockdown recapitulates fin anomalies and enhanced Notch signaling, underscoring an evolutionarily conserved role in appendage development. Collectively, these data fulfill moderate functional criteria concordant with human phenotypes.

Integration of genetic and experimental findings reveals a haploinsufficiency mechanism whereby biallelic LRP4 variants disrupt Wnt modulation, culminating in CLS. The strong segregation in consanguineous kindreds, recurrence of key alleles across populations, and cross-species functional concordance satisfy ClinGen definitive criteria. Genetic testing of LRP4 is recommended for individuals presenting with syndactyly and renal anomalies, and variant interpretation should consider domain localization and functional assay data. Carrier screening in high-risk communities and early prenatal diagnosis can inform reproductive decision-making.

Key take-home: Biallelic LRP4 loss-of-function variants are a definitive cause of autosomal-recessive Cenani-Lenz syndactyly syndrome, with direct implications for molecular diagnosis, genetic counseling, and potential Wnt-targeted therapeutic strategies.

References

• American Journal of Human Genetics • 2010 • LRP4 mutations alter Wnt/beta-catenin signaling and cause limb and kidney malformations in Cenani-Lenz syndrome PMID:20381006
• Genomics • 2006 • Mutations in the gene encoding the low-density lipoprotein receptor LRP4 cause abnormal limb development in the mouse PMID:16517118
• European Journal of Medical Genetics • 2013 • Cenani-Lenz syndrome restricted to limb and kidney anomalies associated with a novel LRP4 missense mutation PMID:23664847
• American Journal of Medical Genetics Part A • 2014 • Truncating mutations in LRP4 lead to a prenatal lethal form of Cenani-Lenz syndrome PMID:24924585
• Clinical Dysmorphology • 2020 • Cenani-Lenz syndactyly in siblings with a novel homozygous LRP4 mutation and recurrent hypoglycaemia PMID:31895055

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