title: ALX4 dysfunction disrupts craniofacial and epidermal development.
abstract: Genetic control of craniofacial morphogenesis requires a complex interaction of numerous genes encoding factors essential for patterning and differentiation. We present two Turkish families with a new autosomal recessive frontofacial dysostosis syndrome characterized by total alopecia, a large skull defect, coronal craniosynostosis, hypertelorism, severely depressed nasal bridge and ridge, bifid nasal tip, hypogonadism, callosal body agenesis and mental retardation. Using homozygosity mapping, we mapped the entity to chromosome 11p11.2-q12.3 and subsequently identified a homozygous c.793C-->T nonsense mutation in the human ortholog of the mouse aristaless-like homeobox 4 (ALX4) gene. This mutation is predicted to result in a premature stop codon (p.R265X) of ALX4 truncating 146 amino acids of the protein including a part of the highly conserved homeodomain and the C-terminal paired tail domain. Although the RNA is stable and not degraded by nonsense-mediated RNA decay, the mutant protein is likely to be non-functional. In a skin biopsy of an affected individual, we observed a hypomorphic interfollicular epidermis with reduced suprabasal layers associated with impaired interfollicular epidermal differentiation. Hair follicle-like structures were present but showed altered differentiation. Our data indicate that ALX4 plays a critical role both in craniofacial development as in skin and hair follicle development in human.
authors.affiliation: Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
authors.forename: Hulya
authors.initials: H
authors.lastname: Kayserili
authors.forename: Elif
authors.initials: E
authors.lastname: Uz
authors.forename: Carien
authors.initials: C
authors.lastname: Niessen
authors.forename: Ibrahim
authors.initials: I
authors.lastname: Vargel
authors.forename: Yasemin
authors.initials: Y
authors.lastname: Alanay
authors.forename: Gokhan
authors.initials: G
authors.lastname: Tuncbilek
authors.forename: Gokhan
authors.initials: G
authors.lastname: Yigit
authors.forename: Oya
authors.initials: O
authors.lastname: Uyguner
authors.forename: Sukru
authors.initials: S
authors.lastname: Candan
authors.forename: Hamza
authors.initials: H
authors.lastname: Okur
authors.forename: Serkan
authors.initials: S
authors.lastname: Kaygin
authors.forename: Sevim
authors.initials: S
authors.lastname: Balci
authors.forename: Emin
authors.initials: E
authors.lastname: Mavili
authors.forename: Mehmet
authors.initials: M
authors.lastname: Alikasifoglu
authors.forename: Ingo
authors.initials: I
authors.lastname: Haase
authors.forename: Bernd
authors.initials: B
authors.lastname: Wollnik
authors.forename: Nurten Ayse
authors.initials: NA
authors.lastname: Akarsu
mesh_terms: D002648:Child; D002675:Child, Preschool; D002874:Chromosome Mapping; D003394:Craniofacial Dysostosis / Q000235:genetics / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics / Q000378:metabolism*; D004817:Epidermis / Q000254:growth & development* / Q000378:metabolism; D005147:Facial Bones / Q000254:growth & development* / Q000378:metabolism*; D006801:Humans; D007223:Infant; D008297:Male; D009154:Mutation; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism*
chemical_list: C416676:ALX4 protein, human; D004268:DNA-Binding Proteins; D014157:Transcription Factors