ALX4 dysfunction disrupts craniofacial and epidermal development

Date

2009-11-01

Author

Kayserili, Hulya
Uz, Elif
Niessen, Carien
VARGEL, İBRAHİM
ALANAY, Yasemin
Tuncbilek, Gokhan
Yigit, Gokhan
Uyguner, Oya
Candan, Sukru
Okur, Hamza
Kaygın, Serkan
Balci, Sevim
Mavili, Emin
Alikasifoglu, Mehmet
Haase, Ingo
Wollnik, Bernd
Akarsu, Nurten Ayse

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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.

URI

https://hdl.handle.net/11511/88604

Journal

HUMAN MOLECULAR GENETICS

DOI

https://doi.org/10.1093/hmg/ddp391

Collections

Graduate School of Informatics, Article

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Citation Formats

H. Kayserili et al., “ALX4 dysfunction disrupts craniofacial and epidermal development,” HUMAN MOLECULAR GENETICS, pp. 4357–4366, 2009, Accessed: 00, 2021. [Online]. Available: https://hdl.handle.net/11511/88604.