Disruption of ALX1 Causes Extreme Microphthalmia and Severe Facial Clefting: Expanding the Spectrum of Autosomal-Recessive ALX-Related Frontonasal Dysplasia

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• 作者：Elif Uz ; Yasemin Alanay ; Dilek Aktas ; Ibrahim Vargel ; Safak Gucer ; Gokhan Tuncbilek ; Ferdin ; von Eggeling ; Engin Yilmaz ; Ozgur Deren ; Nicole Posorski ; Hilal Ozdag ; Thomas Liehr ; Sevim Balci ; Mehmet Al
• 刊名：The American Journal of Human Genetics
• 出版年：2010
• 出版时间：14 May 2010
• 年：2010
• 卷：86
• 期：5
• 页码：789-796
• 全文大小：866 K

文摘

We present an autosomal-recessive frontonasal dysplasia (FND) characterized by bilateral extreme microphthalmia, bilateral oblique facial cleft, complete cleft palate, hypertelorism, wide nasal bridge with hypoplasia of the ala nasi, and low-set, posteriorly rotated ears in two distinct families. Using Affymetrix 250K SNP array genotyping and homozygosity mapping, we mapped this clinical entity to chromosome 12q21. In one of the families, three siblings were affected, and CNV analysis of the critical region showed a homozygous 3.7 Mb deletion containing the ALX1 (CART1) gene, which encodes the aristaless-like homeobox 1 transcription factor. In the second family we identified a homozygous donor-splice-site mutation (c.531+1G > A) in the ALX1 gene, providing evidence that complete loss of function of ALX1 protein causes severe disruption of early craniofacial development. Unlike loss of its murine ortholog, loss of human ALX1 does not result in neural-tube defects; however, it does severely affect the orchestrated fusion between frontonasal, nasomedial, nasolateral, and maxillary processes during early-stage embryogenesis. This study further expands the spectrum of the recently recognized autosomal-recessive ALX-related FND phenotype in humans.