Journal article
Identification of Isthmin 1 as a Novel Clefting and Craniofacial Patterning Gene in Humans
Genetics (Austin), Vol.208(1), pp.283-296
01/2018
DOI: 10.1534/genetics.117.300535
PMCID: PMC5753863
PMID: 29162626
Abstract
Orofacial clefts are one of the most common birth defects, affecting 1-2 per 1000 births, and have a complex etiology. High-resolution array-based comparative genomic hybridization has increased the ability to detect copy number variants (CNVs) that can be causative for complex diseases such as cleft lip and/or palate. Utilizing this technique on 97 nonsyndromic cleft lip and palate cases and 43 cases with cleft palate only, we identified a heterozygous deletion of
in one affected case, as well as a deletion in a second case that removes putative 3' regulatory information.
is a strong candidate for clefting, as it is expressed in orofacial structures derived from the first branchial arch and is also in the same "synexpression group" as
and
and
, all of which have been associated with clefting. CNVs affecting
are exceedingly rare in control populations, and
scores as a likely haploinsufficiency locus. Confirming its role in craniofacial development, knockdown or clustered randomly interspaced short palindromic repeats/Cas9-generated mutation of
in
resulted in mild to severe craniofacial dysmorphologies, with several individuals presenting with median clefts. Moreover, knockdown of
produced decreased expression of
, itself a gene associated with clefting, in regions of the face that pattern the maxilla. Our study demonstrates a successful pipeline from CNV identification of a candidate gene to functional validation in a vertebrate model system, and reveals
as both a new human clefting locus as well as a key craniofacial patterning gene.
Details
- Title: Subtitle
- Identification of Isthmin 1 as a Novel Clefting and Craniofacial Patterning Gene in Humans
- Creators
- Lisa A Lansdon - Interdisciplinary Graduate Program in GeneticsBenjamin W Darbro - Interdisciplinary Graduate Program in GeneticsAline L Petrin - College of Dentistry, University of Iowa, Iowa 52242 andAlissa M Hulstrand - Department of Biology, Northland College, Ashland, Wisconsin 54806Jennifer M Standley - University of IowaRachel B Brouillette - Department of BiologyAbby Long - Department of BiologyM Adela Mansilla - Department of PediatricsRobert A Cornell - Department of Anatomy and Cell Biology, andJeffrey C Murray - College of Dentistry, University of Iowa, Iowa 52242 andDouglas W Houston - Interdisciplinary Graduate Program in GeneticsJ Robert Manak - Interdisciplinary Graduate Program in Genetics
- Resource Type
- Journal article
- Publication Details
- Genetics (Austin), Vol.208(1), pp.283-296
- DOI
- 10.1534/genetics.117.300535
- PMID
- 29162626
- PMCID
- PMC5753863
- NLM abbreviation
- Genetics
- ISSN
- 0016-6731
- eISSN
- 1943-2631
- Publisher
- United States
- Grant note
- T32 GM008629 / NIGMS NIH HHS T90 DE023520 / NIDCR NIH HHS R01 DE021071 / NIDCR NIH HHS
- Language
- English
- Date published
- 01/2018
- Academic Unit
- Medical Genetics and Genomics; Biology; Pediatric Dentistry; Craniofacial Anomalies Research Center; Nursing; Iowa Institute of Human Genetics; Orthodontics; Anatomy and Cell Biology; International Programs; Stead Family Department of Pediatrics; Epidemiology; Public Policy Center (Archive); Dental Research
- Record Identifier
- 9983992094502771
Metrics
59 Record Views