A novel biallelic splice‐site variant in the LRP4 gene causes sclerosteosis 2

Abstract

The LRP4 gene encodes the highly conserved low‐density lipoprotein receptor‐related protein 4 (LRP4), which acts as a co‐receptor for sclerostin. Sclerostin and LRP4 negatively regulate WNT/β‐catenin signaling pathway and lack of their inhibitory activity leads to constant osteoblastic differentiation. Consequently, increased bone formation occurs, which in the case of LRP4 mutations results in sclerosteosis type 2 (SOST2). Alterations within the LRP4 may also cause Cenani‐Lenz syndactyly syndrome (CLSS), congenital myasthenia or isolated syndactyly. Here, we have reported a patient, in whom we found a novel homozygous splice‐site variant c.1048+6T>C in LRP4 using whole exome sequencing. The patient was initially misdiagnosed with isolated CLSS‐like or Malik‐Percin‐like syndactyly. However, we have finally refined the diagnosis after comprehensive radiological examination and molecularly confirmed SOST2. Additionally, we have pointed here to the splicing variants as important causative alterations that may be overlooked in the molecular analysis due to the lack of advanced, reliable algorithms, built‐into the standard diagnostic pipelines. Using advanced in silico prediction tools of splice‐site alterations, including Alamut Visual software, we have demonstrated that the c.1048+6T>C LRP4 variant affects the native donor site and impairs an SC35 enhancer activity. Based on our experience, we recommend comprehensive radiological imaging, including X‐ray of the skull in each case of isolated syndactyly resulting from pathogenic variants of LRP4. We suggest that all previously reported patients carrying biallelic LRP4 mutations, who were diagnosed with isolated syndactyly, could actually present with SOST2 that had been unrecognized due to the incomplete clinical and radiological assessment.

microRNA-136-5p from bone marrow mesenchymal stem cell-derived exosomes facilitates fracture healing by targeting LRP4 to activate the Wnt/β-catenin pathway

“…30 Moreover, LRP4 negatively regulates the Wnt/β-catenin pathway during osteoblastic differentiation. 41 Accumulating evidence continues to demonstrate that the Wnt/β-catenin pathway can promote the proliferation and differentiation of bone cells, and bone formation, thereby facilitating fracture healing. 21,42 Thus, we reasoned that exosome-encapsulated miR-136-5p from BMSCs may promote the osteogenic proliferation and differentiation by targeting the LRP4/Wnt/β-catenin signalling axis.…”

LRP4 mutations, dental anomalies, and oral exostoses

“…Patients with sclerosteosis 2 carrying heterozygous LRP4 variants, however, have also been reported. 25,26 We report five heterozygous missense mutations (p.Leu1356Arg, p.Ala1702Gly, p.Arg263His, p.Gly-1314Ser, and p.Asn1385Ser) in LRP4 in 11 patients from six unrelated Thai families affected with dental anomalies. We hypothesize that these five variants are associated with dental anomalies and are not simply coincidental findings.…”

Identification of Compound Heterozygous Variants in LRP4 Demonstrates That a Pathogenic Variant outside the Third β-Propeller Domain Can Cause Sclerosteosis

“…However, more recently, Bukowska-Olech et al reported on a homozygous splice-site variant (c.1048 + 6 T > C), located before the β-propeller domains of LRP4, in a sclerosteosis patient. As no functional studies were performed, it is unclear whether this identified variant leads to a complete loss of function, and whether it also affects the sclerostin–LRP4 interaction [ 18 ]. In addition to the aforementioned variants in the third β-propeller domain, genetic variation spread across other regions of LRP4 is shown to cause other disorders ( Figure 1 ), such as Cenani–Lenz syndactyly syndrome (OMIM #212780), myasthenia gravis (OMIM #616304), and isolated syndactyly [ 15 , 19 , 20 ].…”