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

Department of Genetics, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia.
The American Journal of Human Genetics (Impact Factor: 10.93). 12/2012; 92(1). DOI: 10.1016/j.ajhg.2012.11.016
Source: PubMed


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.

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Available from: Eissa Faqeih, Dec 12, 2015
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    • "Mutations in GDF6 (MIM#601147) and GDF3 (MIM#606522) have been associated with autosomal dominant KFS [Tassabehji et al., 2008; Ye et al., 2010]. In several consanguineous families, homozygous truncating mutations have been identified in MEOX1 (MIM#600147), which encodes a transcription factor with a wellestablished role in somite development [Bayrakli et al., 2013; Mohamed et al., 2013]. In addition, there are many other types of non-KFS cases of SDV that were also shown to be associated with variants in other genes including DLL3, LFNG, MESP2, HES7, and TBX6 [McInerney-Leo et al., 2015, Wu et al., 2015]. "
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    ABSTRACT: Klippel-Feil syndrome is a rare disorder represented by a subgroup of segmentation defects of the vertebrae and characterized by fusion of the cervical vertebrae, low posterior hairline, and short neck with limited motion. Both autosomal dominant and recessive inheritance patterns were reported in families with Klippel-Feil. Mutated genes for both dominant (GDF6 and GDF3) and recessive (MEOX1) forms of Klippel-Feil syndrome have been shown to be involved in somite development via transcription regulation and signaling pathways. Heterotaxy arises from defects in proteins that function in the development of left-right asymmetry of the developing embryo. We describe a consanguineous family with a male proband who presents with classical Klippel-Feil syndrome together with heterotaxy (situs inversus totalis). The present patient also had Sprengel's deformity, deformity of the sternum, and a solitary kidney. Using exome sequencing, we identified a homozygous frameshift mutation (c.299delT; p.L100fs) in RIPPLY2, a gene shown to play a crucial role in somitogenesis and participate in the Notch signaling pathway via negatively regulating Tbx6. Our data confirm RIPPLY2 as a novel gene for autosomal recessive Klippel-Feil syndrome, and in addition-from a mechanistic standpoint-suggest the possibility that mutations in RIPPLY2 could also lead to heterotaxy. © 2015 Wiley Periodicals, Inc. © 2015 Wiley Periodicals, Inc.
    Full-text · Article · Aug 2015 · American Journal of Medical Genetics Part A
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    • "These genes play important roles in somite development during embryogenesis in vertebrates. However, this syndrome likely has a heterogeneous etiology [27,28]. "
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    ABSTRACT: Dermoid sinus is an uncommon epithelial-lined fistula that may be associated with vertebral malformations. In humans, Klippel-Feil syndrome (KFS) is a rare condition characterized by congenital cervical vertebral fusion and may be associated with other developmental defects, including dermoid sinus. The present case report describes an adult Dachshund with cervical and cranial thoracic vertebral malformations as well as thoracic limb malformations resembling KFS with a concurrent type IV dermoid sinus. A 1.5 year-old Dachshund with congenital thoracic limbs deformities and cervical-thoracic vertebral malformations presented with cervical hyperesthesia, rigidity of the cervical musculature and tetraparesis. Neurologic, radiographic, and computed tomography (CT) (2D, 3D, CT fistulography) examinations revealed skeletal anomalies, a dermoid sinus in the cranial thoracic region and epidural gas within the vertebral canal. Surgical resection and histopathological evaluation of the sinus tract were performed and confirmed a type IV dermoid sinus. The clinical signs progressively recovered postoperatively, and no recurrent signs were observed after 6 months of follow-up. Cervical vertebral malformations associated with limbs anomalies have not been reported in dogs and may represent a condition similar to KFS in humans. KFS can occur concurrently with other congenital conditions including dermoid sinus and should be included among the complex congenital anomalies described in dogs.
    Full-text · Article · Mar 2014 · BMC Veterinary Research
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    • "However, the observed amino acid change was not located within a highly conserved region. Mutations were also identified in the ORMDL3 gene (delCCCATCTTTCCCCAAC in the 3′ UTR), which is associated with susceptibility to asthma, and the GHDC gene (delCAC p.W281del), which has no known functional significance [7,8]. Thus, we excluded these five candidate genes as causative for the KFS phenotype. "
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    ABSTRACT: Klippel-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. We 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. Here, 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.
    Full-text · Article · Sep 2013 · BMC Genetics
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