Significant association between IRF6 820G→A and non-syndromic cleft lip with or without cleft palate in the Thai population

Background: Previous data have shown an association between DNA sequence variants in the IRF6 gene and an increased risk of non-syndromic cleft lip with or without cleft palate (CL/P) in some populations. Objective: To investigate Thai CL/P patients and relative for a 820G→A polymorphism. Subjects: 192 CL/P Thai patients, 177 of their mothers, 73 of their fathers, and 278 controls. Results: There were significant differences in the frequency distributions of both genotypes (p = 0.02) and alleles (p = 0.04) among probands as compared with the control group. The odds ratio calculated for the patients having the GG genotype compared with the other two genotypes (GA and AA) was 1.67 (95% confidence interval, 1.13 to 2.47). This pattern is consistent with a recessive effect of the G allele. No association between any of the parents' genotypes and CL/P was found. The IRF6 820G→A was responsible for 16.7% of the genetic contribution to CL/P. Conclusions: The findings confirm that IRF6 820G→A is associated with CL/P

MBTPS2 mutations cause defective regulated intramembrane proteolysis in X-linked osteogenesis imperfecta

Osteogenesis imperfecta (OI) is a collagen-related bone dysplasia. We identified an X-linked recessive form of OI caused by defects in MBTPS2, which encodes site-2 metalloprotease (S2P). MBTPS2 missense mutations in two independent kindreds with moderate/severe OI cause substitutions at highly conserved S2P residues. Mutant S2P has normal stability, but impaired functioning in regulated intramembrane proteolysis (RIP) of OASIS, ATF6 and SREBP transcription factors, consistent with decreased proband secretion of type I collagen. Further, hydroxylation of the collagen lysine residue (K87) critical for crosslinking is reduced in proband bone tissue, consistent with decreased lysyl hydroxylase 1 in proband osteoblasts. Reduced collagen crosslinks presumptively undermine bone strength. Also, proband osteoblasts have broadly defective differentiation. These mutations provide evidence that RIP plays a fundamental role in normal bone development