Genotype-phenotype correlations in MYCN-related Feingold syndrome.
ABSTRACT Feingold syndrome (FS) is the most frequent cause of familial syndromic gastrointestinal atresia and follows autosomal dominant inheritance. FS is caused by germline mutations in or deletions of the MYCN gene. Previously, 12 different heterozygous MYCN mutations and two deletions containing multiple genes including MYCN were described. All these mutations result in haploinsufficiency of both the canonical MYCN protein and the shorter isoform, DeltaMYCN. We report 11 novel mutations including seven mutations in exon 2 that result in a premature termination codon (PTC) in the long MYCN transcript. Moreover, we have identified a PTC in exon 1 that only affects the DeltaMYCN isoform, without a phenotypic effect. This suggests that mutations in only DeltaMYCN do not contribute to the FS. Additionally, we found three novel deletions encompassing MYCN. Together with our previous report we now have a total of four missense mutations in the DNA binding domain, 19 PTCs of which six render the transcript subject to nonsense-mediated decay (NMD), and five larger deletions in a total of 77 patients. We have reviewed the clinical features of these patients, and found that digital anomalies, e.g., brachymesophalangy and toe syndactyly, are the most consistent features, present in 100% and 97% of the patients, respectively. Small head circumference was present in 89% of the cases. Gastrointestinal atresia remains the most important major congenital anomaly (55%), but cardiac and renal anomalies are also frequent. We suggest that the presence of brachymesophalangy and toe syndactyly in combination with microcephaly is enough to justify MYCN analysis.
SourceAvailable from: José Estevão-Costa[Show abstract] [Hide abstract]
ABSTRACT: Background:Abnormal lung development was recently described in the rat model of esophageal atresia and tracheoesophageal fistula (EA-TEF). Since in this condition the ventral-to-dorsal switch of Shh expression in the foregut is disturbed, the present study tested the hypothesis that this abnormal expression at the emergence of the tracheo-bronchial bud might be translated into the developing lung.Methods:Pregnant rats received either 1.75mg/Kg i.p. adriamycin or vehicle from E7 to E9. Three groups were studied: control, adriamycin-exposed with and without EA-TEF. Embryos were recovered and the lungs were harvested and processed for RT-PCR and immunofluorescence analysis of the Shh signalling cascade.Results:Shh signalling was downregulated at the late embryonic stage of lung development (E13) in embryos with EA-TEF. Throughout the subsequent stages of development the expression of both Shh and its downstream components increased significantly and remained upregulated throughout gestation. Immunofluorescent localization was consistent with these findings.Conclusion:Defective Shh signalling environment in the foregut is present beyond the emergence of lung buds and probably impairs lung development. Later in gestation, lungs exhibited a remarkable ability to upregulate the Shh cascade suggesting a compensatory response. These findings may be relevant to understand pulmonary disease suffered by children with EA-TEF.Pediatric Research (2014); doi:10.1038/pr.2014.105.Pediatric Research 10/2014; 76(4):355-362. DOI:10.1038/pr.2014.105 · 2.84 Impact Factor
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ABSTRACT: Abstract During early and late embryo neurodevelopment, a large number of molecules work together in a spatial and temporal manner to ensure the adequate formation of an organism. Diverse signals participate in embryo patterning and organization synchronized by time and space. Among the molecules that are expressed in a temporal and spatial manner, and that are considered essential in several developmental processes, are the microRNAs (miRNAs). In this review, we highlight some important aspects of the biogenesis and function of miRNAs as well as their participation in ectoderm commitment and their role in central nervous system (CNS) development. Instead of giving an extensive list of miRNAs involved in these processes, we only mention those miRNAs that are the most studied during the development of the CNS as well as the most likely mRNA targets for each miRNA and its protein functions.Reviews in the neurosciences 06/2014; 25(5). DOI:10.1515/revneuro-2014-0014 · 3.31 Impact Factor
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ABSTRACT: Gastrointestinal atresias are a common and serious feature within the spectrum of gastrointestinal malformations. Atresias tend to be lethal, although, now-days surgery and appropriate care can restore function to the affected organs. In spite of their frequency, their life threatening condition and report history gastrointestinal atresias' etiology remains mostly unclarified. Gastrointestinal atresias can occur as sporadic but they are more commonly seen in association with other anomalies. For the syndromic cases there is mounting evidence of a strong genetic component. Sporadic cases are generally thought to originate from mechanical or vascular incidents in utero, especially for the atresias of the lower intestinal tract. However, recent data show that a genetic component may be present also in these cases. Embryological and genetic studies are starting to uncover the mechanism of gastrointestinal development and their genetic components. Here we present an overview of the current knowledge of gastrointestinal atresias, their syndromic forms and the genetic pathways involved in gastrointestinal malformation.European Journal of Medical Genetics 08/2014; DOI:10.1016/j.ejmg.2014.06.007 · 1.49 Impact Factor