ALX4 dysfunction disrupts craniofacial and epidermal development.
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.
Kayserili
Hulya
H
Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul, Turkey.
Uz
Elif
E
Niessen
Carien
C
Vargel
Ibrahim
I
Alanay
Yasemin
Y
Tuncbilek
Gokhan
G
Yigit
Gokhan
G
Uyguner
Oya
O
Candan
Sukru
S
Okur
Hamza
H
Kaygin
Serkan
S
Balci
Sevim
S
Mavili
Emin
E
Alikasifoglu
Mehmet
M
Haase
Ingo
I
Wollnik
Bernd
B
Akarsu
Nurten Ayse
NA
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*
C416676:ALX4 protein, human; D004268:DNA-Binding Proteins; D014157:Transcription Factors