title: Homozygous HOXB1 loss-of-function mutation in a large family with hereditary congenital facial paresis.
abstract: Hereditary congenital facial paresis (HCFP) belongs to the congenital cranial dysinnervation disorders. HCFP is characterized by the isolated dysfunction of the seventh cranial nerve and can be associated with hearing loss, strabismus, and orofacial anomalies. Möbius syndrome shares facial palsy with HCFP, but is additionally characterized by limited abduction of the eye(s). Genetic heterogeneity has been documented for HCFP as one locus mapped to chromosome 3q21-q22 (HCFP1) and a second to 10q21.3-q22.1 (HCFP2). The only known causative gene for HCFP is HOXB1 (17q21; HCFP3), encoding a homeodomain-containing transcription factor of the HOX gene family, which are master regulators of early developmental processes. The previously reported HOXB1 mutations change arginine 207 to another residue in the homeodomain and alter binding capacity of HOXB1 for transcriptional co-regulators and DNA. We performed whole exome sequencing in HCFP-affected individuals of a large consanguineous Moroccan family. The homozygous nonsense variant c.66C>G/p.(Tyr22*) in HOXB1 was identified in the four patients with HCFP and ear malformations, while healthy family members carried the mutation in the heterozygous state. This is the first disease-associated HOXB1 mutation with a likely loss-of-function effect suggesting that all HOXB1 variants reported so far also have severe impact on activity of this transcriptional regulator. © 2016 Wiley Periodicals, Inc.
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: Markus
authors.initials: M
authors.lastname: Vogel
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Eunike
authors.initials: E
authors.lastname: Velleuer
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Leon F
authors.initials: LF
authors.lastname: Schmidt-Jiménez
authors.affiliation: Department of General Pediatrics, Neonatology and Pediatric Cardiology, University Children's Hospital, Heinrich-Heine University, Düsseldorf, Germany.
authors.forename: Ertan
authors.initials: E
authors.lastname: Mayatepek
authors.affiliation: Department of Pediatric Oncology, Hematology and Clinical Immunology, University Children's Hospital, Heinrich Heine University, Düsseldorf, Germany.
authors.forename: Arndt
authors.initials: A
authors.lastname: Borkhardt
authors.affiliation: University Medical Center Hamburg-Eppendorf, Bioinformatics Service Facility, Hamburg, Germany.|Center for Bioinformatics, University of Hamburg, Hamburg, Germany.|Heinrich-Pette-Institute, Leibniz-Institute for Experimental Virology, Virus Genomics, Hamburg, Germany.
authors.forename: Malik
authors.initials: M
authors.lastname: Alawi
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Kerstin
authors.initials: K
authors.lastname: Kutsche
authors.affiliation: Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
authors.forename: Fanny
authors.initials: F
authors.lastname: Kortüm
mesh_terms: D000328:Adult; D002648:Child; D003241:Consanguinity; D059472:Exome / Q000235:genetics*; D005158:Facial Paralysis / Q000151:congenital* / Q000235:genetics / Q000503:physiopathology; D005260:Female; D018740:Genetic Heterogeneity; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D018398:Homeodomain Proteins / Q000235:genetics*; D006720:Homozygote; D006801:Humans; D008297:Male; D009154:Mutation; D014158:Transcription, Genetic
chemical_list: C101121:HOXB1 homeodomain protein; D018398:Homeodomain Proteins
keywords: HOXB1 homeodomain protein; congenital; facial palsy; facial paralysis; genetic testing; genetics