Abstract
Introduction
The human VANGL1 genes has been predicted to be associated with idiopathic scoliosis, as a mutation (c.676C > T, L226F) was identified in a family with dominant inheritance of the disease. A previous investigation of the gene revealed the candidate to segregate, with all but one family member (Sharma, et al. ASHG 2012 Annual Meeting Program Guide. 2012). Adolescent idiopathic scoliosis (AIS) is generally considered multigenetic, but the determining genes remain yet to be characterized. In this study, we have examined VANGL1 as a contributor to the phenotype of AIS.
Materials and Methods
We have conducted automated Sanger sequencing of the seven coding exons of VANGL1 gene in a disease cohort of 170 AIS patients (n = 340) and 177 controls (n = 354). Localization of mutated VANGL1 proteins was investigated in cell systems using immunofluorescence microscopy.
Results
Two novel mutations, each in separate individuals within the considered disease cohort, were identified. One mutation is situated in the third coding exon, which encodes the transmembrane parts of the VANGL1 protein. This mutation is a c.407T > A (I136N) conversion, for which the patient is heterozygotes. Furthermore, this mutation was also identified in the dizygotic unaffected twin of the patient. The second mutation was found in the seventh coding exon, which encodes the C-terminal of the VANGL1 protein. This mutation is a c.1318T > G (F440V) conversion, for which the patient is also heterozygotes. Neither of the identified mutations was present in the sequenced controls or in 2000 Danish exomes (Lohmueller et al. Am J Hum Genet 2013;93:1072–1086). The F440V mutation results in altered localization of the VANGL1 protein, from very clear membrane association to a cytoplasmic distribution, with possible retainment in endoplasmic reticulum and the Golgi apparatus, near the cell nucleus.
Conclusion
Our results show that mutations in the VANGL1 gene can cause AIS and suggest that defects in planar cell polarity may be an underlying cause of AIS. Examination of the expression of VANGL1 in juvenile or adult stages of life is wanted, as well as examinations of effects on downstream targets of mutated VANGL1 and polarity in affected cells.