Mutations in MEOX1, Encoding Mesenchyme Homeobox 1, Cause Klippel-Feil Anomaly

Abstract

Klippel-Feil syndrome (KFS) is a segmentation malformation of the cervical spine; clinically, it manifests as a short neck with reduced mobility and a low posterior hairline. Several genes have been proposed as candidates for KFS when it is present with other associated anomalies, but the genetics of isolated KFS have been difficult to study because of the syndrome's mostly sporadic occurrence. We describe a multiplex consanguineous family in which isolated KFS maps to a single 17q21.31 locus that harbors a homozygous frameshift deletion in MEOX1; this deletion results in complete instability of the transcript. Direct sequencing of this gene in two siblings from another consanguineous family affected by isolated KFS uncovered another homozygous truncating (nonsense) MEOX1 mutation that also leads to complete degradation of the transcript. This gene encodes a transcription factor with a well-established and nonredundant role in somite development, and homozygous null alleles of Meox1 in mice have a cervical skeletal defect that is remarkably similar to the one we observe in human individuals with MEOX1 mutations. Our data strongly suggest that KFS is the human phenotypic equivalent of the sclerotome polarity defect that results from Meox1 deficiency in mice.

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.…”

Anaesthetic Management for Emergency Caesarean Section in a Parturient with Klippel Feil Syndrome

“…But in some people there are no identified mutations in the GDF6 or GDF3 genes and the etiology remains unknown. Mutations in MEOX 1 have been found to occur in association with Klippel-Feil syndrome [3]. Most cases of Klippel Feil are sporadic.…”