Browsing by Author "Golzio, Christelle"

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    Mutations in the endothelin receptor type A cause mandibulofacial dysostosis with alopecia
    (Elsevier, 2015-04-02) Gordon, Christopher T.; Weaver, K. Nicole; Zechi-Ceide, Roseli Maria; Madsen, Erik C.; Tavares, Andre L.P.; Oufadem, Myriam; Kurihara, Yukiko; Adameyko, Igor; Picard, Arnaud; Breton, Sylvain; Pierrot, Se´bastien; Biosse-Duplan, Martin; Voisin, Norine; Masson, Cecile; Bole-Feysot, Christine; Nitschke´, Marie-Ange; Lacombe, Didier; Guion-Almeida, Maria Leine; Moura, Priscila Padilha; Garib, Daniela Gamba; Munnich, Arnold; Ernfors, Patrik; Hufnagel, Robert B.; Hopkin, Robert J.; Kurihara, Hiroki; Saal, Howard M.; Weaver, David D.; Katsanis, Nicholas; Lyonnet, Stanislas; Golzio, Christelle; Clouthier, David E.; Amiel, Jeanne; Department of Medical & Molecular Genetics, IU School of Medicine
    The endothelin receptor type A (EDNRA) signaling pathway is essential for the establishment of mandibular identity during development of the first pharyngeal arch. We report four unrelated individuals with the syndrome mandibulofacial dysostosis with alopecia (MFDA) who have de novo missense variants in EDNRA. Three of the four individuals have the same substitution, p.Tyr129Phe. Tyr129 is known to determine the selective affinity of EDNRA for endothelin 1 (EDN1), its major physiological ligand, and the p.Tyr129Phe variant increases the affinity of the receptor for EDN3, its non-preferred ligand, by two orders of magnitude. The fourth individual has a somatic mosaic substitution, p.Glu303Lys, and was previously described as having Johnson-McMillin syndrome. The zygomatic arch of individuals with MFDA resembles that of mice in which EDNRA is ectopically activated in the maxillary prominence, resulting in a maxillary to mandibular transformation, suggesting that the p.Tyr129Phe variant causes an EDNRA gain of function in the developing upper jaw. Our in vitro and in vivo assays suggested complex, context-dependent effects of the EDNRA variants on downstream signaling. Our findings highlight the importance of finely tuned regulation of EDNRA signaling during human craniofacial development and suggest that modification of endothelin receptor-ligand specificity was a key step in the evolution of vertebrate jaws.
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    Partial uniparental isodisomy of chromosome 16 unmasks a deleterious biallelic mutation in IFT140 that causes Mainzer-Saldino syndrome
    (BMC, 2017-07-19) Helm, Benjamin M.; Willer, Jason R.; Sadeghpour, Azita; Golzio, Christelle; Crouch, Eric; Vergano, Samantha Schrier; Katsanis, Nicholas; Davis, Erica E.; Medical and Molecular Genetics, School of Medicine
    BACKGROUND: The ciliopathies represent an umbrella group of >50 clinical entities that share both clinical features and molecular etiology underscored by structural and functional defects of the primary cilium. Despite the advances in gene discovery, this group of entities continues to pose a diagnostic challenge, in part due to significant genetic and phenotypic heterogeneity and variability. We consulted a pediatric case from asymptomatic, non-consanguineous parents who presented as a suspected ciliopathy due to a constellation of retinal, renal, and skeletal findings. RESULTS: Although clinical panel sequencing of genes implicated in nephrotic syndromes yielded no likely causal mutation, an oligo-SNP microarray identified a ~20-Mb region of homozygosity, with no altered gene dosage, on chromosome 16p13. Intersection of the proband's phenotypes with known disease genes within the homozygous region yielded a single candidate, IFT140, encoding a retrograde intraflagellar transport protein implicated previously in several ciliopathies, including the phenotypically overlapping Mainzer-Saldino syndrome (MZSDS). Sanger sequencing yielded a maternally inherited homozygous c.634G>A; p.Gly212Arg mutation altering the exon 6 splice donor site. Functional studies in cells from the proband showed that the locus produced two transcripts: a majority message containing a mis-splicing event that caused a premature termination codon and a minority message homozygous for the p.Gly212Arg allele. Zebrafish in vivo complementation studies of the latter transcript demonstrated a loss of function effect. Finally, we conducted post-hoc trio-based whole exome sequencing studies to (a) test the possibility of other causal loci in the proband and (b) explain the Mendelian error of segregation for the IFT140 mutation. We show that the proband harbors a chromosome 16 maternal heterodisomy, with segmental isodisomy at 16p13, likely due to a meiosis I error in the maternal gamete. CONCLUSIONS: Using clinical phenotyping combined with research-based genetic and functional studies, we have characterized a recurrent IFT140 mutation in the proband; together, these data are consistent with MZSDS. Additionally, we report a rare instance of a uniparental isodisomy unmasking a deleterious mutation to cause a ciliary disorder.