title: Setleis syndrome: clinical, molecular and structural studies of the first TWIST2 missense mutation.
abstract: Setleis syndrome is characterized by bitemporal scar-like lesions and other characteristic facial features. It results from recessive mutations that truncate critical functional domains in the basic helix-loop-helix (bHLH) transcription factor, TWIST2, which regulates expression of genes for facial development. To date, only four nonsense or small deletion mutations have been reported. In the current report, the clinical findings in a consanguineous Turkish family were characterized. Three affected siblings had the characteristic features of Setleis syndrome. Homozygosity for the first TWIST2 missense mutation, c.326T>C (p.Leu109Pro), was identified in the patients. In silico analyses predicted that the secondary structure of the mutant protein was sustained, but the empirical force field energy increased to an unfavorable level with the proline substitution (p.Leu109Pro). On a crystallographically generated dimer, p.Leu109 lies near the dimer interface, and the proline substitution is predicted to hinder dimer formation. Therefore, p.Leu109Pro-TWIST2 alters the three dimensional structure and is unable to dimerize, thereby hindering the binding of TWIST2 to its target genes involved in facial development.
authors.affiliation: Department of Neurosciences University of California San Diego, San Diego, CA, USA.
authors.forename: R Ozgur
authors.initials: RO
authors.lastname: Rosti
authors.affiliation: Department of Medical Genetics, Istanbul University, Istanbul Medical Faculty, Istanbul Turkey.
authors.forename: Z Oya
authors.initials: ZO
authors.lastname: Uyguner
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Irina
authors.initials: I
authors.lastname: Nazarenko
authors.affiliation: Department of Plastic, Reconstructive and Aesthetic Surgery, Necmettin Erbakan University, Meram Faculty of Medicine, Konya, Turkey.
authors.forename: Mehmet
authors.initials: M
authors.lastname: Bekerecioglu
authors.affiliation: Department of Biochemistry, University of Puerto Rico School of Medicine, San Juan, PR, USA.
authors.forename: Carmen L
authors.initials: CL
authors.lastname: Cadilla
authors.affiliation: Department of Medical Genetics, Istanbul University, Istanbul Medical Faculty, Istanbul Turkey.
authors.forename: Hilal
authors.initials: H
authors.lastname: Ozgur
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.|Department of Pediatrics, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
authors.forename: Beom Hee
authors.initials: BH
authors.lastname: Lee
authors.affiliation: Department of Structural and Chemical Biology, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Aneel K
authors.initials: AK
authors.lastname: Aggarwal
authors.affiliation: Department of Medical Biology, Istanbul University, Istanbul Medical Faculty, Istanbul, Turkey.
authors.forename: Sacide
authors.initials: S
authors.lastname: Pehlivan
authors.affiliation: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Desnick
mesh_terms: D000293:Adolescent; D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D002648:Child; D003198:Computer Simulation; D003461:Crystallography; D004476:Ectodermal Dysplasia; D005260:Female; D005489:Focal Dermal Hypoplasia / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D000090303:Focal Facial Dermal Dysplasias; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010375:Pedigree; D012097:Repressor Proteins / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D012871:Skin Diseases / Q000175:diagnosis / Q000235:genetics* / Q000473:pathology; D014421:Turkey; D051879:Twist-Related Protein 1 / Q000235:genetics* / Q000378:metabolism; D044465:White People / Q000235:genetics
chemical_list: D012097:Repressor Proteins; C486274:TWIST2 protein, human; D051879:Twist-Related Protein 1
keywords: Setleis syndrome; TWIST2; bHLH domain; facial development; inborn error of development; missense mutation; molecular modeling