title: Frontorhiny, a distinctive presentation of frontonasal dysplasia caused by recessive mutations in the ALX3 homeobox gene.
abstract: We describe a recessively inherited frontonasal malformation characterized by a distinctive facial appearance, with hypertelorism, wide nasal bridge, short nasal ridge, bifid nasal tip, broad columella, widely separated slit-like nares, long philtrum with prominent bilateral swellings, and midline notch in the upper lip and alveolus. Additional recurrent features present in a minority of individuals have been upper eyelid ptosis and midline dermoid cysts of craniofacial structures. Assuming recessive inheritance, we mapped the locus in three families to chromosome 1 and identified mutations in ALX3, which is located at band 1p13.3 and encodes the aristaless-related ALX homeobox 3 transcription factor. In total, we identified seven different homozygous pathogenic mutations in seven families. These mutations comprise missense substitutions at critical positions within the conserved homeodomain as well as nonsense, frameshift, and splice-site mutations, all predicting severe or complete loss of function. Our findings contrast with previous studies of the orthologous murine gene, which showed no phenotype in Alx3(-/-) homozygotes, apparently as a result of functional redundancy with the paralogous Alx4 gene. We conclude that ALX3 is essential for normal facial development in humans and that deficiency causes a clinically recognizable phenotype, which we term frontorhiny.
authors.affiliation: Weatherall Institute of Molecular Medicine, University of Oxford, Oxford OX3 9DS, UK.
authors.forename: Stephen R F
authors.initials: SR
authors.lastname: Twigg
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Versnel
authors.forename: Gudrun
authors.initials: G
authors.lastname: Nürnberg
authors.forename: Melissa M
authors.initials: MM
authors.lastname: Lees
authors.forename: Meenakshi
authors.initials: M
authors.lastname: Bhat
authors.forename: Peter
authors.initials: P
authors.lastname: Hammond
authors.forename: Raoul C M
authors.initials: RC
authors.lastname: Hennekam
authors.forename: A Jeannette M
authors.initials: AJ
authors.lastname: Hoogeboom
authors.forename: Jane A
authors.initials: JA
authors.lastname: Hurst
authors.forename: David
authors.initials: D
authors.lastname: Johnson
authors.forename: Alexis A
authors.initials: AA
authors.lastname: Robinson
authors.forename: Peter J
authors.initials: PJ
authors.lastname: Scambler
authors.forename: Dianne
authors.initials: D
authors.lastname: Gerrelli
authors.forename: Peter
authors.initials: P
authors.lastname: Nürnberg
authors.forename: Irene M J
authors.initials: IM
authors.lastname: Mathijssen
authors.forename: Andrew O M
authors.initials: AO
authors.lastname: Wilkie
mesh_terms: D002648:Child; D002878:Chromosomes, Human, Pair 1 / Q000235:genetics; D019465:Craniofacial Abnormalities / Q000235:genetics*; D018398:Homeodomain Proteins / Q000235:genetics*; D006801:Humans; D007231:Infant, Newborn; D009154:Mutation; D009295:Nasal Bone / Q000002:abnormalities*
chemical_list: C485163:ALX3 protein, human; D018398:Homeodomain Proteins