scholarly journals Familial cleft tongue caused by a unique translation initiation codon variant in TP63

2021 ◽  
Author(s):  
Julia Schmidt ◽  
Gudrun Schreiber ◽  
Janine Altmüller ◽  
Holger Thiele ◽  
Peter Nürnberg ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Cleft Lip ◽  
Initiation Codon ◽  
Foot Deformities ◽  
Whole Exome ◽  
Heterozygous Variant ◽  
Cleft Lip Palate ◽  
Translation Initiation Codon ◽  
Malformation Syndromes ◽  
Cleft Tongue

AbstractVariants in transcription factor p63 have been linked to several autosomal dominantly inherited malformation syndromes. These disorders show overlapping phenotypic characteristics with various combinations of the following features: ectodermal dysplasia, split-hand/foot malformation/syndactyly, lacrimal duct obstruction, hypoplastic breasts and/or nipples, ankyloblepharon filiforme adnatum, hypospadias and cleft lip/palate. We describe a family with six individuals presenting with a striking novel phenotype characterized by a furrowed or cleft tongue, a narrow face, reddish hair, freckles and various foot deformities. Whole-exome sequencing (WES) identified a novel heterozygous variant, c.3G>T, in TP63 affecting the translation initiation codon (p.1Met?). Sanger sequencing confirmed dominant inheritance of this unique variant in all six affected family members. In summary, our findings indicate that heterozygous variants in TP63 affecting the first translation initiation codon result in a novel phenotype dominated by a cleft tongue, expanding the complex genotypic and phenotypic spectrum of TP63-associated disorders.

scholarly journals The Role of eIF1 in Translation Initiation Codon Selection in Caenorhabditiselegans

Genetics ◽  
2010 ◽  
Vol 186 (4) ◽  
pp. 1187-1196 ◽  
Author(s):  
Lisa L. Maduzia ◽  
Anais Moreau ◽  
Nausicaa Poullet ◽  
Sebastien Chaffre ◽  
Yinhua Zhang
Keyword(s):  
Translation Initiation ◽  
Initiation Codon ◽  
Translation Initiation Codon ◽  
Codon Selection

Juberg-Hayward syndrome is a cohesinopathy, caused by mutation in ESCO2

2020 ◽  
Author(s):  
Piranit Nik Kantaputra ◽  
Prapai Dejkhamron ◽  
Worrachet Intachai ◽  
Chumpol Ngamphiw ◽  
Katsushige Kawasaki ◽  
...  
Keyword(s):  
Short Stature ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Upper Limb ◽  
Autosomal Recessive ◽  
Cleft Lip ◽  
Clinical Findings ◽  
Protein Model ◽  
Whole Exome ◽  
Cleft Lip Palate

Summary Background Juberg-Hayward syndrome (JHS; MIM 216100) is a rare autosomal recessive malformation syndrome, characterized by cleft lip/palate, microcephaly, ptosis, short stature, hypoplasia or aplasia of thumbs, and dislocation of radial head and fusion of humerus and radius leading to elbow restriction. Objective To report for the first time the molecular aetiology of JHS. Patient and methods Clinical and radiographic examination, whole exome sequencing, Sanger sequencing, mutant protein model construction, and in situ hybridization of Esco2 expression in mouse embryos were performed. Results Clinical findings of the patient consisted of repaired cleft lip/palate, microcephaly, ptosis, short stature, delayed bone age, hypoplastic fingers and thumbs, clinodactyly of the fifth fingers, and humeroradial synostosis leading to elbow restriction. Intelligence is normal. Whole exome sequencing of the whole family showed a novel homozygous base substitution c.1654C>T in ESCO2 of the proband. The sister was homozygous for the wildtype variant. Parents were heterozygous for the mutation. The mutation is predicted to cause premature stop codon p.Arg552Ter. Mutations in ESCO2, a gene involved in cohesin complex formation, are known to cause Roberts/SC phocomelia syndrome. Roberts/SC phocomelia syndrome and JHS share similar clinical findings, including autosomal recessive inheritance, short stature, cleft lip/palate, severe upper limb anomalies, and hypoplastic digits. Esco2 expression during the early development of lip, palate, eyelid, digits, upper limb, and lower limb and truncated protein model are consistent with the defect. Conclusions Our study showed that Roberts/SC phocomelia syndrome and JHS are allelic and distinct entities. This is the first report demonstrating that mutation in ESCO2 causes JHS, a cohesinopathy.

Novel Mutation of the Translation Initiation Codon of the α1-Globin Gene (ATG>AAG orHBA1:c.2T>A)

Hemoglobin ◽  
2016 ◽  
Vol 40 (5) ◽  
pp. 369-370 ◽  
Author(s):  
John S. Waye ◽  
Barry Eng ◽  
Meredith Hanna ◽  
Betty-Ann Hohenadel ◽  
Lisa Nakamura ◽  
...  
Keyword(s):  
Translation Initiation ◽  
Novel Mutation ◽  
Globin Gene ◽  
Initiation Codon ◽  
Translation Initiation Codon

Loss of the Gata1 Gene IE Exon Leads to Variant Transcript Expression and the Production of GATA1 Protein Lacking the N-Terminal Domain.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3648-3648
Author(s):  
Eri Kobayashi ◽  
Ritsuko Shimizu ◽  
Yuko Kikuchi ◽  
Satoru Takahashi ◽  
Masayuki Yamamoto
Keyword(s):  
Gene Expression ◽  
Translation Initiation ◽  
Knockout Mice ◽  
Conflicts Of Interest ◽  
Hematopoietic Cells ◽  
Full Length ◽  
Initiation Codon ◽  
Severe Thrombocytopenia ◽  
Exon 2 ◽  
Translation Initiation Codon

Abstract Abstract 3648 Poster Board III-584 GATA1 is a transcription factor essential for the differentiation of erythroid cells and megakaryocytes. Since GATA1 regulates genes related to the survival, proliferation and differentiation of hematopoietic cells, regulation of the Gata1 gene expression is critically important for the understanding of hematopoiesis. The Gata1 locus contains multiple untranslated first exons plus five common coding exons. Of these first exons, erythroid first exon (IE exon) is important for the Gata1 gene expression in the hematopoietic lineages. However, due to the embryonic lethality of this IE exon knockdown mice, less is understood about the contribution of the IE exon to adult hematopoiesis. Here, we achieved specific deletion of the IE exon in adulthood by crossing the IE-floxed mice with the interferon-inducible Mx1-Cre transgenic mice. This conditional IE-deletion mouse (ΔIE mouse) showed severe thrombocytopenia with increased premature megakaryocytes similarly to the phenotypes reported in the conditional Gata1 knockout mice in which the entire Gata1 gene was deleted in adulthood. In addition, the ΔIE mice showed severe anemia with skewed erythroid maturation, and importantly this erythroid phenotypes substantially differed from those observed in the conditional Gata1 knockout mice. Further analyses revealed that the Gata1 mRNA level in the megakaryocytic lineage was significantly downregulated. By contrast, in the erythroid lineage, Gata1 mRNA was retained at a comparable level to that in control mice utilizing two alternative first exons; one was the IEb/c, which was previously reported as a first exon rarely used in hematopoietic cells, and the other was newly identified IEd exon located within the second intron. Surprisingly, in the ΔIE mice these transcripts failed to produce full-length GATA1 protein, but instead inefficiently yielded GATA1 lacking the N-terminal 83 amino acids. This form of GATA1 is often observed in Down syndrome-associated transient myeloproliferative disorder and acute megakaryoblastic leukemia. Of note, the transcript derived from exon IEb/c preserved the first translation initiation codon in exon 2 but lost the potential to select the first translation initiation codon or failed to produce full-length GATA1. The present study demonstrates that the IE exon is instrumental to adult erythropoiesis by regulating the proper level of transcription and by selecting the correct translation start site for production of adequate full-length GATA1 protein. Disclosures: No relevant conflicts of interest to declare.

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