Dominant frontonasal dysplasia with ectodermal defects results from increased activity of ALX4

Author:

Peled Alon1ORCID,Sarig Ofer1ORCID,Mohamad Janan12ORCID,Eskin‐Schwartz Marina34ORCID,Vodo Dan1ORCID,Bochner Ron1ORCID,Malchin Natalya1ORCID,Isakov Ofer567,Shomron Noam2ORCID,Fainberg Gilad8ORCID,Bertolini Marta910ORCID,Paus Ralf101112ORCID,Sprecher Eli12ORCID

Affiliation:

1. Division of Dermatology Tel Aviv Sourasky Medical Center Tel Aviv Israel

2. Department of Human Molecular Genetics and Biochemistry Tel‐Aviv University Tel Aviv Israel

3. Faculty of Health Sciences Ben Gurion University of the Negev Be'er Sheva Israel

4. Soroka University Medical Center Genetic Institute Be'er Sheva Israel

5. Rabin Medical Center Raphael Recanati Genetic Institute Petach Tikva Israel

6. Clalit Research Institute, Clalit Health Services Ramat Gan Israel

7. The Ivan and Francesca Berkowitz Family Living Laboratory Collaboration at Harvard Medical School and Clalit Research Institute Boston Massachusetts USA

8. Department of Ophthalmology Tel Aviv Sourasky Medical Center Tel Aviv Israel

9. Department of Dermatology University of Münster Münster Germany

10. Monasterium Laboratory, Nano‐Bioanalytik Zentrum Münster Germany

11. Dr Phillip Frost Department of Dermatology & Cutaneous Surgery University of Miami Miller School of Medicine Florida USA

12. Centre for Dermatology Research, Institute of Inflammation and Repair University of Manchester Manchester UK

Abstract

AbstractFrontonasal dysplasia (FND) refers to a group of rare developmental disorders characterized by abnormal morphology of the craniofacial region. We studied a family manifesting with clinical features typical for FND2 including neurobehavioral abnormalities, hypotrichosis, hypodontia, and facial dysmorphism. Whole‐exome sequencing analysis identified a novel heterozygous frameshift insertion in ALX4 (c.985_986insGTGC, p.Pro329Argfs*115), encoding aristaless homeobox 4. This and a previously reported dominant FND2‐causing variant are predicted to result in the formation of a similar abnormally elongated protein tail domain. Using a reporter assay, we showed that the elongated ALX4 displays increased activity. ALX4 negatively regulates the Wnt/β‐catenin pathway and accordingly, patient keratinocytes showed altered expression of genes associated with the WNT/β‐catenin pathway, which in turn may underlie ectodermal manifestations in FND2. In conclusion, dominant FND2 with ectodermal dysplasia results from frameshift variants in ALX4 exerting a gain‐of‐function effect.

Publisher

Wiley

Subject

Genetics (clinical),Genetics

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