Deficiency of the Cytoskeletal Protein SPECC1L Leads to Oblique Facial Clefting

Irfan Saadi; Fowzan S Alkuraya; Stephen S Gisselbrecht; Wolfram Goessling; Resy Cavallesco; Annick Turbe-Doan; Aline L Petrin; James Harris; Ursela Siddiqui; Arthur W Grix; Hanne D Hove; Philippe Leboulch; Thomas W Glover; Cynthia C Morton; Antonio Richieri-Costa; Jeffrey C Murray; Robert P Erickson; Richard L Maas

doi:10.1016/j.ajhg.2011.05.023

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Deficiency of the Cytoskeletal Protein SPECC1L Leads to Oblique Facial Clefting

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Deficiency of the Cytoskeletal Protein SPECC1L Leads to Oblique Facial Clefting

Irfan Saadi, Fowzan S Alkuraya, Stephen S Gisselbrecht, Wolfram Goessling, Resy Cavallesco, Annick Turbe-Doan, Aline L Petrin, James Harris, Ursela Siddiqui, Arthur W Grix, …

American journal of human genetics, Vol.89(1), pp.44-55

07/15/2011

DOI: 10.1016/j.ajhg.2011.05.023

PMCID: PMC3135813

PMID: 21703590

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Abstract

Genetic mutations responsible for oblique facial clefts (ObFC), a unique class of facial malformations, are largely unknown. We show that loss-of-function mutations in SPECC1L are pathogenic for this human developmental disorder and that SPECC1L is a critical organizer of vertebrate facial morphogenesis. During murine embryogenesis, Specc1l is expressed in cell populations of the developing facial primordial, which proliferate and fuse to form the face. In zebrafish, knockdown of a SPECC1L homolog produces a faceless phenotype with loss of jaw and facial structures, and knockdown in Drosophila phenocopies mutants in the integrin signaling pathway that exhibit cell-migration and -adhesion defects. Furthermore, in mammalian cells, SPECC1L colocalizes with both tubulin and actin, and its deficiency results in defective actin-cytoskeleton reorganization, as well as abnormal cell adhesion and migration. Collectively, these data demonstrate that SPECC1L functions in actin-cytoskeleton reorganization and is required for proper facial morphogenesis.

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Title: Subtitle: Deficiency of the Cytoskeletal Protein SPECC1L Leads to Oblique Facial Clefting
Creators: Irfan Saadi - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Fowzan S Alkuraya - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Stephen S Gisselbrecht - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Wolfram Goessling - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Resy Cavallesco - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Annick Turbe-Doan - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Aline L Petrin - Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA
James Harris - Department of Experimental Pathology, Beth Israel Deaconess Medical Center, Boston, MA 02115, USA
Ursela Siddiqui - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Arthur W Grix - Department of Genetics, Sacramento Medical Center, Kaiser Permanente, Sacramento, CA 95815, USA
Hanne D Hove - Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet, DK-2100, DK-2100 Copenhagen, Denmark
Philippe Leboulch - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Thomas W Glover - Department of Human Genetics, University of Michigan, Ann Arbor, MI 48109, USA
Cynthia C Morton - Department of Obstetrics and Gynecology and Reproductive Biology and Department of Pathology, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Antonio Richieri-Costa - Department Serviço de Genética Clinica. Hospital de Anomalias Craniofaciais, Universidade de Saõ Paulo, Bauru, SP 17012, Brazil
Jeffrey C Murray - Department of Pediatrics, University of Iowa, Iowa City, IA 52242, USA
Robert P Erickson - Department of Pediatrics, Section of Medical and Molecular Genetics and Department of Molecular and Cellular Biology, The University of Arizona, Tucson, AZ 85724, USA
Richard L Maas - Division of Genetics, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, MA 02115, USA
Resource Type: Journal article
Publication Details: American journal of human genetics, Vol.89(1), pp.44-55
DOI: 10.1016/j.ajhg.2011.05.023
PMID: 21703590
PMCID: PMC3135813
NLM abbreviation: Am J Hum Genet
ISSN: 0002-9297
eISSN: 1537-6605
Publisher: Elsevier Inc
Language: English
Date published: 07/15/2011
Academic Unit: Orthodontics; Anatomy and Cell Biology; Stead Family Department of Pediatrics; Epidemiology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Dental Research
Record Identifier: 9984025359202771

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