Functional analysis of candidate genes in 2q13 deletion syndrome implicates FBLN7 and TMEM87B deficiency in congenital heart defects and FBLN7 in craniofacial malformations

Mark W Russell; Maide O Raeker; Sarah B Geisler; Peedikayil E Thomas; Tracy A Simmons; John A Bernat; Thor Thorsson; Jeffrey W Innis

doi:10.1093/hmg/ddu144

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Functional analysis of candidate genes in 2q13 deletion syndrome implicates FBLN7 and TMEM87B deficiency in congenital heart defects and FBLN7 in craniofacial malformations

Journal article

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Peer reviewed

Functional analysis of candidate genes in 2q13 deletion syndrome implicates FBLN7 and TMEM87B deficiency in congenital heart defects and FBLN7 in craniofacial malformations

Mark W Russell, Maide O Raeker, Sarah B Geisler, Peedikayil E Thomas, Tracy A Simmons, John A Bernat, Thor Thorsson and Jeffrey W Innis

Human molecular genetics, Vol.23(16), pp.4272-4284

08/15/2014

DOI: 10.1093/hmg/ddu144

PMID: 24694933

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Abstract

Recurrent 2q13 deletion syndrome is associated with incompletely penetrant severe cardiac defects and craniofacial anomalies. We used an atypical, overlapping 1.34 Mb 2q13 deletion in a patient with pathogenically similar congenital heart defects (CHD) to narrow the putative critical region for CHD to 474 kb containing six genes. To determine which of these genes is responsible for severe cardiac and craniofacial defects noted in the patients with the deletions, we used zebrafish morpholino knockdown to test the function of each orthologue during zebrafish development. Morpholino-antisense-mediated depletion of fibulin-7B, a zebrafish orthologue of fibulin-7 (FBLN7), resulted in cardiac hypoplasia, deficient craniofacial cartilage deposition and impaired branchial arch development. TMEM87B depletion likewise resulted in cardiac hypoplasia but with preserved branchial arch development. Depletion of both fibulin-7B and TMEM87B resulted in more severe defects of cardiac development, suggesting that their concurrent loss may enhance the risk of a severe cardiac defect. We postulate that heterozygous loss of FBLN7 and TMEM87B account for some of the clinical features, including cardiac defects and craniofacial abnormalities associated with 2q13 deletion syndrome.

Chromosome Deletion

Oligonucleotides, Antisense

Membrane Proteins - genetics

Humans

Calcium-Binding Proteins - deficiency

Male

Zebrafish - embryology

Syndrome

Zebrafish - genetics

Chromosomes, Human, Pair 2

Heart Defects, Congenital - genetics

Membrane Proteins - deficiency

Animals

Female

Morpholinos

Zebrafish Proteins - genetics

Craniofacial Abnormalities - genetics

Infant, Newborn

Calcium-Binding Proteins - genetics

Details

Title: Subtitle: Functional analysis of candidate genes in 2q13 deletion syndrome implicates FBLN7 and TMEM87B deficiency in congenital heart defects and FBLN7 in craniofacial malformations
Creators: Mark W Russell - Departments of Pediatrics and mruss@med.umich.edu innis@umich.edu
Maide O Raeker - Departments of Pediatrics and
Sarah B Geisler - Departments of Pediatrics and
Peedikayil E Thomas - Human Genetics, University of Michigan Ann Arbor, MI, USA
Tracy A Simmons - Departments of Pediatrics and
John A Bernat - Departments of Pediatrics and
Thor Thorsson - Departments of Pediatrics and
Jeffrey W Innis - Departments of Pediatrics and Human Genetics, University of Michigan Ann Arbor, MI, USA mruss@med.umich.edu innis@umich.edu
Resource Type: Journal article
Publication Details: Human molecular genetics, Vol.23(16), pp.4272-4284
DOI: 10.1093/hmg/ddu144
PMID: 24694933
ISSN: 0964-6906
eISSN: 1460-2083
Language: English
Date published: 08/15/2014
Academic Unit: Stead Family Department of Pediatrics; Medical Genetics and Genomics
Record Identifier: 9984093367602771

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