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1.
Mol Syndromol ; 10(1-2): 40-47, 2019 Feb.
Article En | MEDLINE | ID: mdl-30976278

Craniofrontonasal syndrome (CFNS) is an X-linked disorder caused by EFNB1 mutations in which females are more severely affected than males. Severe male phenotypes are associated with mosaicism, supporting cellular interference for sex bias in this disease. Although many variants have been found in the coding region of EFNB1, only 2 pathogenic variants have been identified in the same nucleotide in 5'UTR, disrupting the stop codon of an upstream open reading frame (uORF). uORFs are known to be part of a wide range of post-transcriptional regulation processes, and just recently, their association with human diseases has come to light. In the present study, we analyzed EFNB1 in a female patient with typical features of CFNS. We identified a variant, located at c.-411, creating a new upstream ATG (uATG) in the 5'UTR of EFNB1, which is predicted to alter an existing uORF. Dual-luciferase reporter assays showed significant reduction in protein translation, but no difference in the mRNA levels. Our study demonstrates, for the first time, the regulatory impact of uATG formation on EFNB1 levels and suggests that this should be the target region in molecular diagnosis of CFNS cases without pathogenic variants in the coding and splice sites regions of EFNB1.

2.
Am J Med Genet A ; 173(4): 938-945, 2017 Apr.
Article En | MEDLINE | ID: mdl-28328130

Auriculocondylar syndrome, mainly characterized by micrognathia, small mandibular condyle, and question mark ears, is a rare disease segregating in an autosomal dominant pattern in the majority of the families reported in the literature. So far, pathogenic variants in PLCB4, GNAI3, and EDN1 have been associated with this syndrome. It is caused by a developmental abnormality of the first and second pharyngeal arches and it is associated with great inter- and intra-familial clinical variability, with some patients not presenting the typical phenotype of the syndrome. Moreover, only a few patients of each molecular subtype of Auriculocondylar syndrome have been reported and sequenced. Therefore, the spectrum of clinical and genetic variability is still not defined. In order to address these questions, we searched for alterations in PLCB4, GNAI3, and EDN1 in patients with typical Auriculocondylar syndrome (n = 3), Pierre Robin sequence-plus (n = 3), micrognathia with additional craniofacial malformations (n = 4), or non-specific auricular dysplasia (n = 1), which could represent subtypes of Auriculocondylar syndrome. We found novel pathogenic variants in PLCB4 only in two of three index patients with typical Auriculocondylar syndrome. We also performed a detailed comparative analysis of the patients presented in this study with those previously published, which showed that the pattern of auricular abnormality and full cheeks were associated with molecularly characterized individuals with Auriculocondylar syndrome. Finally, our data contribute to a better definition of a set of parameters for clinical classification that may be used as a guidance for geneticists ordering molecular testing for Auriculocondylar syndrome. © 2017 Wiley Periodicals, Inc.


Ear Diseases/diagnosis , Ear/abnormalities , Genetic Predisposition to Disease , Micrognathism/diagnosis , Mutation , Phospholipase C beta/genetics , Pierre Robin Syndrome/diagnosis , Adult , Child , Ear/pathology , Ear Diseases/classification , Ear Diseases/genetics , Ear Diseases/pathology , Endothelin-1/genetics , Female , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Gene Expression , Genes, Dominant , High-Throughput Nucleotide Sequencing , Humans , Male , Micrognathism/classification , Micrognathism/genetics , Micrognathism/pathology , Pedigree , Phenotype , Pierre Robin Syndrome/classification , Pierre Robin Syndrome/genetics , Pierre Robin Syndrome/pathology , Terminology as Topic
3.
Eur J Hum Genet ; 23(4): 481-5, 2015 Apr.
Article En | MEDLINE | ID: mdl-25026904

Auriculocondylar syndrome is a rare craniofacial disorder comprising core features of micrognathia, condyle dysplasia and question mark ear. Causative variants have been identified in PLCB4, GNAI3 and EDN1, which are predicted to function within the EDN1-EDNRA pathway during early pharyngeal arch patterning. To date, two GNAI3 variants in three families have been reported. Here we report three novel GNAI3 variants, one segregating with affected members in a family previously linked to 1p21.1-q23.3 and two de novo variants in simplex cases. Two variants occur in known functional motifs, the G1 and G4 boxes, and the third variant is one amino acid outside of the G1 box. Structural modeling shows that all five altered GNAI3 residues identified to date cluster in a region involved in GDP/GTP binding. We hypothesize that all GNAI3 variants lead to dominant negative effects.


Ear Diseases/genetics , Ear/abnormalities , GTP-Binding Protein alpha Subunits, Gi-Go/genetics , Genetic Variation , Branchial Region/metabolism , Brazil , Ear Diseases/diagnosis , Female , Humans , Male , Pedigree , Phenotype , Protein Conformation
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