Heterozygous Recurrent Mutations Inducing Dysfunction of Gene in Patients With Short Stature.

PURPOSE

ROR2, a member of the ROR family, is essential for skeletal development as a receptor of Wnt5a. The present study aims to investigate the mutational spectrum of in children with short stature and to identify the underlying molecular mechanisms.

METHODS

We retrospectively analyzed clinical phenotype and whole-exome sequencing (WES) data of 426 patients with short stature through mutation screening of . We subsequently examined the changes in protein expression and subcellular location in caused by the mutations. The mRNA expression of downstream signaling molecules of the Wnt5a-ROR2 pathway was also examined.

RESULTS

We identified 12 mutations in in 21 patients, including 10 missense, one nonsense, and one frameshift. Among all missense variants, four recurrent missense variants [c.1675G > A(p.Gly559Ser), c.2212C > T(p.Arg738Cys), c.1930G > A(p.Asp644Asn), c.2117G > A(p.Arg706Gln)] were analyzed by experiments . The c.1675G > A mutation significantly altered the expression and the cellular localization of the ROR2 protein. The c.1675G > A mutation also caused a significantly decreased expression of c-Jun. In contrast, other missense variants did not confer any disruptive effect on the biological functions of ROR2.

CONCLUSION

We expanded the mutational spectrum of in patients with short stature. Functional experiments potentially revealed a novel molecular mechanism that the c.1675G > A mutation in might affect the expression of downstream Wnt5a-ROR2 pathway gene by disturbing the subcellular localization and expression of the protein.