Asunto(s)
Mutación , Somitos/embriología , Somitos/metabolismo , Columna Vertebral/embriología , Columna Vertebral/metabolismo , Animales , Tipificación del Cuerpo/genética , Regulación del Desarrollo de la Expresión Génica , Genes Homeobox , Ratones , Modelos Animales , Receptores Notch/genética , Receptores Notch/metabolismo , Transducción de Señal , Proteínas Wnt/genética , Proteínas Wnt/metabolismoRESUMEN
Mutations in the Notch1 receptor and delta-like 3 (Dll3) ligand cause global disruptions in axial segmental patterning. Genetic interactions between members of the notch pathway have previously been shown to cause patterning defects not observed in single gene disruptions. We examined Dll3-Notch1 compound mouse mutants to screen for potential gene interactions. While mice heterozygous at either locus appeared normal, 30% of Dll3-Notch1 double heterozygous animals exhibited localized, segmental anomalies similar to human congenital vertebral defects. Unexpectedly, double heterozygous mice also displayed statistically significant reduction of mandibular height and decreased length of the [corrected] maxillary hard palate. Examination of somite-stage embryos and perinatal anatomy and histology did not reveal any organ defects, so we used microarray-based analysis of Dll3 and Notch1 mutant embryos to identify gene targets that may be involved in notch-regulated segmental or craniofacial development. Thus, Dll3-Notch1 double heterozygous mice model human congenital scoliosis and craniofacial disorders.
Asunto(s)
Anomalías Congénitas/genética , Anomalías Craneofaciales/genética , Péptidos y Proteínas de Señalización Intracelular/genética , Proteínas de la Membrana/genética , Receptor Notch1/genética , Escoliosis/genética , Animales , Tipificación del Cuerpo , Cefalometría , Anomalías Congénitas/embriología , Modelos Animales de Enfermedad , Regulación del Desarrollo de la Expresión Génica , Heterocigoto , Humanos , Péptidos y Proteínas de Señalización Intracelular/metabolismo , Mandíbula/anomalías , Proteínas de la Membrana/metabolismo , Ratones , Ratones Mutantes , Análisis de Secuencia por Matrices de Oligonucleótidos , Paladar Duro/anomalías , Receptor Notch1/metabolismo , Costillas/anomalías , Columna Vertebral/anomalíasRESUMEN
STUDY DESIGN: A radiographic analysis of the cervical spine of 70 patients diagnosed with fibrodysplasia ossificans progressiva (FOP) and 33 diagnosed with Klippel-Feil (KF) syndrome was conducted. OBJECTIVES: The objectives of this study were to describe cervical spine abnormalities in patients with FOP, to compare and contrast those findings with the malformations in patients with KF syndrome, and to examine the possible etiology of these abnormalities. SUMMARY OF BACKGROUND DATA: Congenital features of diseases often provide seminal clues to underlying etiology and developmental pathways. While progressive metamorphosis of connective tissue to heterotopic bone is the most dramatic and disabling feature of FOP, less severe congenital anomalies of the skeleton are also present. Vertebral fusions observed in KF are consistent with defects in embryonic segmentation. METHODS: The cervical spine plain films of 70 FOP patients and 33 KF patients with documented congenital abnormalities were reviewed. RESULTS: Generalized neck stiffness and decreased range of motion were noted in most children with FOP. In the FOP patient group, characteristic anomalies, including large posterior elements, tall narrow vertebral bodies,and fusion of the facet joints between C2 and C7, were observed. Most notably, these characteristic anomalies of the cervical spine in patients with FOP were distinctly different from those of 33 patients with KF that were examined but were strikingly similar to those seen in mice with homozygous deletions of the gene-encoding noggin, a bone morphogenetic protein (BMP) antagonist. CONCLUSIONS: FOP patients exhibit a characteristic set of congenital spine malformations. While the noggin gene (NOG) is not mutated in patients who have FOP, these findings extend a growing body of evidence implicating overactivity of the BMP signaling pathway in the molecular pathogenesis of FOP.
Asunto(s)
Proteínas Morfogenéticas Óseas , Vértebras Cervicales/anomalías , Síndrome de Klippel-Feil/patología , Miositis Osificante/patología , Adolescente , Adulto , Animales , Proteínas Morfogenéticas Óseas/antagonistas & inhibidores , Proteínas Morfogenéticas Óseas/genética , Proteínas Morfogenéticas Óseas/metabolismo , Proteínas Portadoras/genética , Niño , Preescolar , Diagnóstico Diferencial , Femenino , Humanos , Lactante , Síndrome de Klippel-Feil/metabolismo , Síndrome de Klippel-Feil/fisiopatología , Masculino , Ratones , Persona de Mediana Edad , Rigidez Muscular/etiología , Rigidez Muscular/fisiopatología , Miositis Osificante/metabolismo , Miositis Osificante/fisiopatología , Rango del Movimiento Articular , Transducción de SeñalRESUMEN
The etiology of congenital scoliosis is largely unknown. The severe vertebral disorder, spondylocostal dysostosis type 1, is associated with a homozygous delta-like 3 (DLL3) mutation. Scoliosis has been observed in a heterozygous DLL3 carrier, raising the possibility of its involvement in congenital scoliosis. We present the first molecular study of congenital scoliosis by analysis of the candidate gene DLL3 and demonstrate one novel missense variant. However, no novel or previously described mutations are present in our cohort, indicating that DLL3 mutations may not be a major cause of congenital scoliosis. Additionally, we have evaluated patients with congenital scoliosis not diagnosed with a known syndrome and identified a significant number of associated renal and cardiac anomalies and familial incidence of idiopathic scoliosis in this group.
Asunto(s)
Proteínas de la Membrana/genética , Escoliosis/genética , Anomalías Múltiples/genética , Estudios de Cohortes , Humanos , Péptidos y Proteínas de Señalización Intracelular , Mutación , SíndromeRESUMEN
The developmental and genetic etiology of most congenital vertebral malformation disorders remains unknown. The objective of this study was to evaluate and classify congenital vertebral defect cases into groupings based on developmental etiology for clinical genetic studies. This classification is intended to be distinct from but complementary to traditional groupings based on spinal curvature or progression. In the first step of this analysis, the authors identified 84 cases of vertebral segmentation disorders by radiologic screening and prospectively recruited 39 of these patients into a clinical genetic study. Next, the authors quantified the extent of contiguous defects and organized cases by craniocaudal localization. Finally, the authors used available clinical association data to identify syndromic and nonsyndromic subcategories, and identified a high rate of orthopaedic and neurologic associations in nonsyndromic patients. This type of analysis has identified subgroups of patients with multiple, contiguous segmental defects and orthopaedic associations that are particularly suitable for further genetic analysis.