Human Molecular Genetics Advance Access originally published online on August 19, 2009
Human Molecular Genetics 2009 18(22):4357-4366; doi:10.1093/hmg/ddp391
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ALX4 dysfunction disrupts craniofacial and epidermal development
1 Department of Medical Genetics, Istanbul Medical Faculty, Istanbul University, Istanbul 34094, Turkey, 2 Department of Medical Genetics, 3 Gene Mapping Laboratory, Pediatric Hematology Unit, 4 Department of Plastic and Reconstructive Surgery and 5 Genetics Unit, Department of Pediatrics, Hacettepe University, Medical Faculty, Ankara 06100, Turkey, 6 Department of Dermatology, 7 Center for Molecular Medicine Cologne (CMMC), 8 Institute of Human Genetics and 9 Cologne Excellence Cluster on Cellular Stress Responses in Aging-Associated Diseases (CECAD), University of Cologne, Cologne 50931, Germany, 10 Hemosoft, Inc., Ankara 06100, Turkey and 11 Department of Plastic and Reconstructive Surgery, Kirikkale University, Medical Faculty, Kirikkale 71000, Turkey
* To whom correspondence should be addressed at: Department of Medical Genetics, Hacettepe University Medical Faculty, Sihhiye, Ankara 06100, Turkey. Tel: +90 3123052559 (N.A.A.)/+49 22147886817 (B.W.); Fax: +90 3124268592 (N.A.A.)/+49 22147886812 (B.W.); Email: nakarsu{at}hacettepe.edu.tr (N.A.A.) or bwollnik{at}uni-koeln.de (B.W.)
Received April 13, 2009; Revised August 7, 2009; Accepted August 13, 2009
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.
The authors wish it to be known that, in their opinion, the first two and the last two authors should be regarded as joint Authors.