Genotype-phenotype correlations in MYCN-related Feingold syndrome

Department of Human Genetics, Radboud University Nijmegen Medical Centre, Nijmegen, the Netherlands.
Human Mutation (Impact Factor: 5.14). 09/2008; 29(9):1125-32. DOI: 10.1002/humu.20750
Source: PubMed


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.

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    • "miR-92a is a member of the miR-17/92 cluster, one of the best studied miRNA clusters, which is involved in cell cycle, proliferation, apoptosis, and other crucial processes , such as normal embryo development ( Mogilyansky and Rigoutsos, 2013 ). Interestingly, this is the first group of miRNAs to be implicated in a human syndrome (Feingold syndrome, characterized by digital anomalies, microcephaly, facial dysmorphism, gastrointestinal atresias , and mild to moderate learning disability) ( Marcelis et al., 2008 ). A direct participation of miR-92 in neuron maturation was assessed in primary cultures of postmitotic CGNs of 8-day-old rats ( Barbato et al., 2010 ). "
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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 · 3.33 Impact Factor
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    • "MYCN (or N-myc proto-oncogene that encodes a protein with a basic helix–loop–helix domain) is ubiquitously expressed in early development and at Carnegie stage 15 is differentially and highly expressed in the esophageal and bronchial epithelia. Furthermore, targeted inactivation of the orthologous murine N-myc gene revealed its function in the development of the gut and in the branching morphogenesis of the lung, in a way that mutant mice with 25% of wild-type levels of N-myc protein are unable to breathe because of severe deficiency in lung branching (46, 47). CHD7 (chromodomain helicase DNA-binding protein 7) is expressed in organs affected by CHARGE syndrome but is widely expressed during fetal development with high levels in epithelial cells of the lung and gut (48). "
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    ABSTRACT: Esophageal atresia with or without tracheoesophageal fistula (EA ± TEF) occurs in 1 out of every 3000 births. Current survival approaches 95%, and research is therefore focused on morbidity and health-related quality of life issues. Up to 50% of neonates with EA ± TEF have one or more additional malformations including those of the respiratory tract that occur in a relatively high proportion of them and particularly of those with vertebral, anal, cardiac, tracheoesophageal, renal, and limb association. Additionally, a significant proportion of survivors suffer abnormal pulmonary function and chronic respiratory tract disease. The present review summarizes the current knowledge about the nature of these symptoms in patients treated for EA ± TEF, and explores the hypothesis that disturbed development and maturation of the respiratory tract could contribute to their pathogenesis.
    Frontiers in Pediatrics 05/2014; 2:39. DOI:10.3389/fped.2014.00039
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    • "Mutation of N-myc in humans causes FS with its very large range of birth defects in a host of tissues [41]. Interestingly the range of defects in constitutive N-myc KO mice are remarkably similar to that of FS [42]. While these findings suggest a conserved role for N-myc in both human and mouse NSC that drives brain growth, the mechanisms have remained somewhat unclear. "
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    ABSTRACT: Separate murine knockout (KO) of either c- or N-myc genes in neural stem and precursor cells (NSC) driven by nestin-cre causes microcephaly. The cerebellum is particularly affected in the N-myc KO, leading to a strong reduction in cerebellar granule neural progenitors (CGNP) and mature granule neurons. In humans, mutation of N-myc also causes microcephaly in Feingold Syndrome. We created a double KO (DKO) of c- and N-myc using nestin-cre, which strongly impairs brain growth, particularly that of the cerebellum. Granule neurons were almost absent from the Myc DKO cerebellum, and other cell types were relatively overrepresented, including astroglia, oligodendrocytes, and Purkinje neurons. These findings are indicative of a profound disruption of cell fate of cerebellar stem and precursors. DKO Purkinje neurons were strikingly lacking in normal arborization. Inhibitory neurons were ectopic and exhibited very abnormal GAD67 staining patterns. Also consistent with altered cell fate, the adult DKO cerebellum still retained a residual external germinal layer (EGL). CGNP in the DKO EGL were almost uniformly NeuN and p27KIP1 positive as well as negative for Math1 and BrdU at the peak of normal cerebellar proliferation at P6. The presence of some mitotic CGNP in the absence of S phase cells suggests a possible arrest in M phase. CGNP and NSC metabolism also was affected by loss of Myc as DKO cells exhibited weak nucleolin staining. Together these findings indicate that c- and N-Myc direct cerebellar development by maintaining CGNP and NSC populations through inhibiting differentiation as well as directing rapid cell cycling and active cellular metabolism. Electronic supplementary material The online version of this article (doi:10.1007/s12311-010-0190-9) contains supplementary material, which is available to authorized users.
    The Cerebellum 12/2010; 9(4):537-47. DOI:10.1007/s12311-010-0190-9 · 2.72 Impact Factor
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