RESUMEN
Rare mutations in IRF6 and GRHL3 cause Van der Woude syndrome, an autosomal dominant orofacial clefting disorder. Common variants in IRF6 and GRHL3 also contribute risk for isolated orofacial clefting. Similarly, variants within genes that encode receptor tyrosine kinase (RTK) signaling components, including members of the FGF pathway, EPHA3 and SPRY2, also contribute risk for isolated orofacial clefting. In the mouse, loss of Irf6 or perturbation of Fgf signaling leads to abnormal oral epithelial adhesions and cleft palate. Oral adhesions can result from a disruption of periderm formation. Here, we find that IRF6 and SPRY4 signaling interact in periderm function. We crossed Irf6 heterozygous ( Irf6+/-) mice with transgenic mice that express Spry4 in the basal epithelial layer ( TgKRT14::Spry4). While embryos with either of these mutations can have abnormal oral adhesions, using a new quantitative assay, we observed a nonadditive effect of abnormal oral epithelial adhesions in the most severely affected double mutant embryos ( Irf6+/-;TgKRT14::Spry4). At the molecular level, the sites of abnormal oral adhesions maintained periderm-like cells that express keratin 6, but we observed abnormal expression of GRHL3. Together, these data suggest that Irf6 and RTK signaling interact in regulating periderm differentiation and function, as well as provide a rationale to screen for epistatic interactions between variants in IRF6 and RTK signaling pathway genes in human orofacial clefting populations.
Asunto(s)
Labio Leporino/genética , Fisura del Paladar/genética , Factores Reguladores del Interferón/genética , Proteínas del Tejido Nervioso/genética , Adherencias Tisulares/genética , Anomalías Múltiples/embriología , Anomalías Múltiples/genética , Animales , Labio Leporino/embriología , Fisura del Paladar/embriología , Quistes/embriología , Quistes/genética , Modelos Animales de Enfermedad , Anomalías Maxilomandibulares/embriología , Anomalías Maxilomandibulares/genética , Labio/anomalías , Labio/embriología , Ratones , Ratones Transgénicos , Anomalías de la Boca/embriología , Anomalías de la Boca/genética , Mutación , Fenotipo , Transducción de Señal , Adherencias Tisulares/embriologíaRESUMEN
Missense mutations in the 3' end of the p63 gene are associated with either RHS (Rapp-Hodgkin syndrome) or AEC (Ankyloblepharon Ectodermal defects Cleft lip/palate) syndrome. These mutations give rise to mutant p63alpha protein isoforms with dominant effects towards their wild-type counterparts. Here we report four RHS/AEC-like patients with mutations (p.Gln9fsX23, p.Gln11X, p.Gln16X), that introduce premature termination codons in the N-terminal part of the p63 protein. These mutations appear to be incompatible with the current paradigms of dominant-negative/gain-of-function outcomes for other p63 mutations. Moreover it is difficult to envisage how the remaining small N-terminal polypeptide contributes to a dominant disease mechanism. Primary keratinocytes from a patient containing the p.Gln11X mutation revealed a normal and aberrant p63-related protein that was just slightly smaller than the wild-type p63. We show that the smaller p63 protein is produced by translation re-initiation at the next downstream methionine, causing truncation of a non-canonical transactivation domain in the DeltaN-specific isoforms. Interestingly, this new DeltaDeltaNp63 isoform is also present in the wild-type keratinocytes albeit in small amounts compared with the p.Gln11X patient. These data establish that the p.Gln11X-mutation does not represent a null-allele leading to haploinsufficiency, but instead gives rise to a truncated DeltaNp63 protein with dominant effects. Given the nature of other RHS/AEC-like syndrome mutations, we conclude that these mutations affect only the DeltaNp63alpha isoform and that this disruption is fundamental to explaining the clinical characteristics of these particular ectodermal dysplasia syndromes.
Asunto(s)
Anomalías Múltiples/genética , Codón sin Sentido , Displasia Ectodérmica/genética , Proteínas de la Membrana/genética , Anomalías de la Boca/genética , Biosíntesis de Proteínas , Anomalías Múltiples/metabolismo , Adolescente , Secuencia de Aminoácidos , Animales , Secuencia de Bases , Línea Celular Tumoral , Células Cultivadas , Niño , Preescolar , Displasia Ectodérmica/metabolismo , Femenino , Humanos , Queratinocitos/metabolismo , Masculino , Proteínas de la Membrana/química , Proteínas de la Membrana/metabolismo , Ratones , Datos de Secuencia Molecular , Anomalías de la Boca/embriología , Anomalías de la Boca/metabolismo , Alineación de Secuencia , Transcripción Genética , Activación TranscripcionalRESUMEN
Persistence of the buccopharyngeal membrane (BPM) also called the oropharyngeal membrane is a rare congenital oropharyngeal anomaly. We report a case of an adult aboriginal male patient with a membrane that closed his oropharyngeal isthmus except for a 2 cm diameter central perforation. The patient had no symptoms related to this membrane and no other congenital anomalies were found. This finding has not previously been reported in an adult. The embryology and management of this rare condition is discussed.
Asunto(s)
Anomalías de la Boca/embriología , Orofaringe/anomalías , Adulto , Trastornos de Deglución/embriología , Humanos , Masculino , Orofaringe/embriologíaRESUMEN
Craniofacial birth defects are the fourth most common congenital anomaly in newborns. Cleft lip and cleft palate (CL/CP) are the most common and immediately recognizable craniofacial anomalies. Some are diagnosed prenatally on ultrasound; more often, they are first noted in the delivery room. The infant may have a cleft that is unilateral, bilateral, complete, or incomplete, and it may involve the lip only, the palate only, or both. Cleft lip and/or cleft palate are often isolated nonsyndromic occurrences; however, when associated with other abnormal physical findings, a recognizable syndrome may be present. Part 1 of this 2-part article describes the incidence of CL/CP. The embryology of the face, lip, and palate are reviewed to enhance the understanding of the timing, complexity, and factors that may influence the development of this lesion. The emerging genetic links, environmental influences, and potential teratogens that may interact to contribute to CL/CP are discussed. Part 2 of this series will provide clinicians with tools to perform a focused risk assessment and obtain a detailed family and pregnancy history to evaluate for known associated risk factors for CL/CP. The article provides a guide for a systematic physical examination of infants with CL/CP. Careful assessment for other midline defects or physical findings consistent with associated syndromes is also discussed. Pictorial examples of a variety of forms of CL/CP are provided to enhance understanding of the spectrum of this defect. Treatment and long-term complications of CL/CP are reviewed with an emphasis on family support, identifying educational resources, and counseling.
Asunto(s)
Anomalías de la Boca/embriología , Anomalías de la Boca/genética , Labio Leporino/embriología , Labio Leporino/genética , Fisura del Paladar/embriología , Fisura del Paladar/genética , Humanos , Recién NacidoRESUMEN
Despite the fact that orofacial clefts represent one of the most common birth defects, the molecular mechanisms by which the embryonic primordia of the midface grow and differentiate are not completely understood. A multiplicity of genes must be expressed and their protein products must interact in a highly orchestrated fashion to affect normal orofacial development. Several families of growth factors have emerged as key contributors to the choreography of cellular and tissue interactions contributing to morphogenesis of the orofacial region. This overview focuses on those growth factors that are generally accepted as playing a pivotal role in normal as well as abnormal development of first branchial arch-derived structures. Particular emphasis is given transforming growth factor-beta (TGF beta) and TGF alpha family members, as these have been the most extensively investigated with regard to their role in development of orofacial structures. Consideration is also given to evidence implicating developmental contributions from members of the bone morphogenetic protein and fibroblast growth factor families.
Asunto(s)
Desarrollo Maxilofacial/fisiología , Boca/embriología , Factor de Crecimiento Transformador alfa/fisiología , Factor de Crecimiento Transformador beta/fisiología , Animales , Femenino , Humanos , Microscopía Electrónica de Rastreo , Modelos Anatómicos , Modelos Biológicos , Boca/efectos de los fármacos , Boca/fisiología , Anomalías de la Boca/embriología , Anomalías de la Boca/patología , Anomalías de la Boca/ultraestructura , Embarazo , Factor de Crecimiento Transformador alfa/efectos adversos , Factor de Crecimiento Transformador beta/efectos adversosAsunto(s)
Anomalías de la Boca/diagnóstico , Anomalías Dentarias/diagnóstico , Anodoncia/diagnóstico , Anodoncia/genética , Niño , Preescolar , Labio Leporino/diagnóstico , Labio Leporino/genética , Fisura del Paladar/diagnóstico , Fisura del Paladar/genética , Femenino , Humanos , Maloclusión/diagnóstico , Maloclusión/genética , Anomalías de la Boca/embriología , Anomalías de la Boca/prevención & control , Embarazo , Anomalías Dentarias/genética , Anomalías Dentarias/prevención & control , Ultrasonografía PrenatalRESUMEN
Major congenital synechiae of the oral cavity constitute a clinically confusing spectrum of abnormalities. On the basis of clinical data, we propose two categories: 1) abnormalities secondary to persistence of the buccopharyngeal membrane and 2) abnormalities secondary to formation of ectopic membranes. An ectopic membrane results from abnormal fusion and can be subclassified as a subglossopalatal membrane, glossopalatal ankylosis, or syngnathia. This classification is supported by embryologic studies and is used to reclassify all cases reported since 1900. Distinct differences, such as the presence of associated limb anomalies, emerge; these are reviewed and add support to the proposed classification.
Asunto(s)
Anomalías Maxilomandibulares/clasificación , Anomalías de la Boca/clasificación , Adherencias Tisulares/congénito , Anomalías Múltiples , Femenino , Humanos , Recién Nacido , Anomalías Maxilomandibulares/embriología , Masculino , Anomalías de la Boca/embriologíaRESUMEN
Using data from the Italian Multicentric Birth Defect Registry a case-control study was performed to verify if chorionic villus sampling (CVS) was associated with transverse limb defects (TLD), with or without features of oro-mandibular-limb hypogenesis complex (OMLHC), in the exposed offspring. The results show that the risk of TLD and OMLHC is increased following CVS, and is particularly high for CVS performed early in pregnancy, i.e., under 70 days of gestational age. These results, together with a review of other epidemiologic studies, biological data and clinical reports, strongly suggest a causative role of CVS as a risk factor for TLD and indicate that at this stage CVS before 70 days of gestational age should be discouraged as an option for prenatal diagnosis and that all patients wishing to undergo CVS should be informed about the possible risk of the procedure.