Mutation in MEOX1 gene causes a recessive Klippel-Feil syndrome subtype

Abstract

BackgroundKlippel-Feil syndrome (KFS) is characterized by the developmental failure of the cervical spine and has two dominantly inherited subtypes. Affected individuals who are the children of a consanguineous marriage are extremely rare in the medical literature, but the gene responsible for this recessive trait subtype of KFS has recently been reported.ResultsWe identified a family with the KFS phenotype in which their parents have a consanguineous marriage. Radiological examinations revealed that they carry fusion defects and numerical abnormalities in the cervical spine, scoliosis, malformations of the cranial base, and Sprengel’s deformity. We applied whole genome linkage and whole-exome sequencing analysis to identify the chromosomal locus and gene mutated in this family. Whole genome linkage analysis revealed a significant linkage to chromosome 17q12-q33 with a LOD score of 4.2. Exome sequencing identified the G > A p.Q84X mutation in the MEOX1 gene, which is segregated based on pedigree status. Homozygous MEOX1 mutations have reportedly caused a similar phenotype in knockout mice.ConclusionsHere, we report a truncating mutation in the MEOX1 gene in a KFS family with an autosomal recessive trait. Together with another recently reported study and the knockout mouse model, our results suggest that mutations in MEOX1 cause a recessive KFS phenotype in humans.

Novel cancer stem cell targets during epithelial to mesenchymal transition in PTEN-deficient trastuzumab-resistant breast cancer

“…In patients, homozygous truncation mutations in the MEOX1 gene cause an autosomal-recessive form of Klippel-Feil Syndrome, a disease characterized by fusion of cervical vertebrae [42, 43]. Recent evidence in zebra fish demonstrates MEOX1+ cells also regulate normal hematopoietic stem cell formation in a cytokine dependent manner [44].…”

Diagnostic strategy in segmentation defect of the vertebrae: a retrospective study of 73 patients

“…The first case was a homozygous MEOX1 variant in a young patient with a very short neck, severely reduced mobility of the neck due to fusion of cervical vertebra and a low posterior hairline corresponding to Klippel-Feil syndrome. This MEOX1 mutation had already been identified by WES and associated with Klippel-Feil syndrome in one consanguineous family with a similar phenotype8 and in a multiplex consanguineous family 30. Inactivation of MEOX1 in mice causes defects in morphogenesis of the second branchial arch, giving an abnormal shape of the basioccipital bone 29.…”

“…The PolyPhen-2 score was 1.00 (probably damaging) and the variant was present at a frequency of 0.0000587245 in the ExAC database in the heterozygous state; no homozygous patients were reported in the ExAC database. Biallelic variants in MEOX1 have already been reported in Klippel-Feil syndrome,8 and we classified this variant as likely pathogenic since its variant was rare in population databases and close to an already-known pathogenic missense variant. The two variants are in trans, concordant with familial segregation.…”

“…Multiple SDV (M-SDV) has been identified in various syndromes and a topographical classification was proposed, separating cervical, thoracic, lumbar and sacral M-SDV. Well-described syndromes are found in each category, notably with Klippel-Feil syndrome, which is associated with variants in GDF3 , GDF6 , MYO18B and MEOX1 8; spondylocarpotarsal synostosis syndrome, associated with variants in FLNB 9; and Currarino syndrome, associated with variants in MNX1 10. M-SDV can also be secondary to neuromuscular disorders and teratogenic exposure (alcohol, valproic acid, phenytoin…) 11.…”

Enhanced Identification of Potential Pleiotropic Genetic Variants for Bone Mineral Density and Breast Cancer

“…MEOX1 is the nearest gene to the pleiotropic SNP rs 4793019 and was one of the genes that were partially validated in our BMD gene expressional validation assay. Mutation in MEOX1 gene was involved in Klippel-Feil syndrome - a skeleton disease with abnormal fusion of two or more cervical vertebras [45]. In a recent study, MEOX1 was proved to be a key molecular target that regulating breast cancer stem cells and was associated with worse clinical survival in BC patients [46].…”