Abstract
Duane retraction syndrome (DRS) is a neuromuscular dysfunction of the eyes. Although many causative genes of DRS have been identified in Europe and the United States, few reports have been published in regard to Chinese DRS. The aim of the present study was to explore the genetic defect of DRS in a Chinese family. Exome sequencing was used to identify the disease-causing gene for the two affected family members. Ophthalmic and physical examinations, as well as genetic screenings for variants in chimerin 1 (CHN1), were performed for all family members. Functional analyses of a CHN1 variant in 293T cells included a Rac-GTP activation assay, α2-chimaerin translocation assay, and co-immunoprecipitation assay. Genetic analysis revealed a NM_001822.7: c.637T > G variant in the CHN1 gene, which resulted in the substitution of a highly conserved C1 domain with valine at codon 213 (NP_001813.1: p.(Phe213Val)) (ClinVar Accession Number: SCV001335305). In-silico analysis revealed that the p.(Phe213Val) substitution affected the protein stability and connections among the amino acids of CHN1 in terms of its tertiary protein structure. Functional studies indicated that the p.(Phe213Val) substitution reduced Rac-GTP activity and enhanced membrane translocation in response to phorbol-myristoyl acetate (PMA). Together with previous studies, our present findings demonstrate that CHN1 may be an important causative gene for different ethnicities with DRS.
Highlights
Duane retraction syndrome (DRS) is a congenital disorder that impairs eye movement[1] and is caused by a failure of the sixth cranial nerve
There were 37 members in the Han Chinese family who were considered for the present study, with 11 members being diagnosed with DRS during childhood
All three types of DRS were detected in our pedigree, which is consistent with previous observations that have suggested phenotypic diversity of DRS12,13
Summary
Duane retraction syndrome (DRS) is a congenital disorder that impairs eye movement[1] and is caused by a failure of the sixth cranial nerve (i.e., the abducens nerve). Based on the current understanding of the genetics of DRS, at least six genes—spalt like transcription factor 4 (SALL4), chimerin 1 (CHN1), homeobox A1 (HOXA1), MAF bZIP transcription factor B (MAFB), kinesin family member 21A (KIF21A), and tubulin beta 3 class III (TUBB3)—have been identified to be associated with DRS4,5. Duane retraction syndrome 2 (DURS2, OMIM 604356) and DURS3 (OMIM 617041) have been identified to be caused by variants in CHN1 and MAFB, while DURS1 (OMIM 126800) maps to chromosome 8q13. Variants in CHN1 hyper-activating α2-chimaerin are involved in familial non-syndromic DURS2 with incomplete penetrance[6]. There are currently no reports regarding genetic abnormalities underlying DRS2 in a Chinese population. The purpose of the present study was to screen for variants in DRS causal genes in a Han Chinese DRS family and to explore the functional mechanism of a novel CHN1 substitution, NM_001822.7: c.637T > G, NP_001813.1: p.(Phe213Val) (ClinVar Accession Number: SCV001335305), underlying DRS2
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