CRELD1

Non syndromic associated CHDs overview

AVSD: atrial & ventricular components (complete) (2, 33.3%)

AVSD: isolated atrial component (primum ASD) (4, 66.7%)

[edit] Synopsis

Rupp et al., 2002 identified CRELD1 as a candidate gene for the AVSD2 locus on chromosome 3p25 based on physical mapping to that locus and studies demonstrating expression in the developing AV endocardial cushions. CRELD1 encodes a cell surface protein that likely functions as a cell adhesion molecule.

[edit] Mutation screens

Analysis of patients with 3p deletion has provided the clue to the identification of the 'AVSD2 gene', CRELD1 (Green et al., 2000). Robinson SW et al., 2003 identified mutations in CRELD1 in 2 out of 22 unrelated subjects with partial AVSD and in 1 out of 11 patients with partial AVSD associated with heterotaxia. Subsequently, Zatyka et al., 2005 detected a novel mutation in 1 out of 49 subjects with AVSD. The index case presented with a partial isolated AVSD and a 47,XXX karyotype. However, mutation analysis of GATA4 and CRELD1 by Sarkozy A et al., 2005 in 42 subjects with non-syndromic AVSD (26 sporadic cases and 16 patients from 9 families) did not reveal any pathogenic mutation in either the GATA4 or CRELD1 gene. Posch MG et al., 2008 analyzed the coding region of GATA4, NKX2.5, CRELD1 and BMP4 in 205 patients with congenital septal defects (110 patients with isolated ASDII (4/110 familial), 60 ASDII, 22 perimembranous VSD, and 13 AVSD and concomitant minor cardiac malformations (CoAo, PDA, or PAPVR). Analysis of CRELD1 as well as NKX2.5 and BMP4 did not result in identification of any further disease-associated mutations. Subsequently, Posch MG et al. investigated wether non-synonymous SNPs may represent susceptibility variants for congenital septal defects and genotyped 360 control alleles deriving from unaffected individuals. However, no significant differences in allele frequencies between cases and controls were observed. Finally, Maslen CL et al., 2006 suggested that mutations in CRELD1 may contribute to the pathogenesis of AVSD in the context of trisomy 21.

External references for CRELD1

• ensembl: ENSG00000163703
• OMIM: 607170
• Search miRBase for CRELD1
• Expression patterns from 4DXPress: CRELD1
• MGI: MGI:2152539
• ZFIN:
• Wikipedia: CRELD1
• Search Wikiproteins: CRELD1
• Search Genetic Association Database: CRELD1
• Search GeneTests: CRELD1
• CHeartED:

Known phenotypes for CRELD1

Non-syndromic

AVSD: atrial & ventricular components (complete)

Support: likely: 2 or more patients (with CHD and a mutation in the candidate gene) References: PMID:17036335 (population study with screening of similar CHD patients and normal controls ) Inheritence: Complete atrioventricular septal defect (OMIM:600309) Incidence: Maslen CL et al., 2006 identified 2 mutations in 2 out of 39 subjects with complete AVSD and Down Syndrome, suggesting that mutations in CRELD1 may contribute to the pathogenesis of AVSD in the context of trisomy 21. Comments: Studies: (1) [ show ] [ hide ] Reference: PMID:17036335 Incidence: 2/39 patients Comments: Maslen CL et al., 2006 identified 2 mutations in 2 out of 39 subjects with complete AVSD and Down Syndrome, suggesting that mutations in CRELD1 may contribute to the pathogenesis of AVSD in the context of trisomy 21. Add another study.

AVSD: isolated atrial component (primum ASD)

Support: confirmed: 2 or more independent reports > 1% incidence References: PMID:12632326 (population study with screening of similar CHD patients and normal controls ) PMID:15857420 (population study with screening of similar CHD patients and normal controls ) Inheritence: Partial atrioventricular septal defect (OMIM:606217): primum ASD Incidence: Robinson SW et al., 2003 performed mutation analysis of CRELD1 in 50 unrelated subjects with nonsyndromic AVSD. Mutations were identified in 2 out of 22 unrelated subjects with partial AVSD and in 1 out of 11 patients with partial AVSD associated with heterotaxia. Zatyka et al., 2005 detected a novel mutation in 1 out of 49 subjects with AVSD. The index case presented with a partial isolated AVSD and a 47,XXX karyotype. Comments: Studies: (2) [ show ] [ hide ] Reference: PMID:12632326 Incidence: 3/33 patients Comments: Robinson SW et al., 2003 performed mutation analysis of CRELD1 in 50 unrelated subjects with nonsyndromic AVSD. Mutations were identified in 2 out of 22 unrelated subjects with partial AVSD and in 1 out of 11 patients with partial AVSD associated with heterotaxia. Reference: PMID:15857420 Incidence: 1/27 patients Comments: Zatyka et al., 2005 detected a novel mutation in 1 out of 49 subjects with AVSD (14 with isolated complete AVSD, 6 with complete AVSD and another cardiac anomaly, 27 with isolated partial AVSD and two with partial AVSD and another cardiac anomaly). The index case presented with a partial isolated AVSD and a 47,XXX karyotype. Add another study.

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Syndromic

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Protein interaction partners

Patients reports for CRELD1

• case 58 Clinical data Phenotype

• case 96 Clinical data Phenotype

• case 1007 Clinical data Phenotype

• case 1504 Clinical data Phenotype

Translocations

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Mutations in CRELD1

Mutation (DNA)	Mutation (peptide)	CHD	Reference	Other features	Inheritence	Additional info.
AF452623:c.1566G>A	AAM75206.1:p.107R>H	AVSD: isolated atrial component (primum ASD)	PMID:12632326	Partial AVSD and heterotaxy (dextrocardia, right ventricle aorta with pulmonary atresia, and a right aortic arch).	Dominant Sporadic	show hide Genetic evidence no parental DNA and data available; 0/200 normal African American controls; 0/100 normal Hispanic controls in silico prediction This mutation results in a substitution of histidine for arginine (R107H) in the highly conserved WE domain. Functional studies Comments
c.484C>G	p.162P>A	AVSD: isolated atrial component (primum ASD)	PMID:15857420	Partial AVSD and 47,XXX	Dominant Sporadic	show hide Genetic evidence inherited from unaffected mother and maternal grandmother; 0/200 normal controls in silico prediction Functional studies Comments
c.4148C>T	p.311T>I	AVSD: isolated atrial component (primum ASD)	PMID:12632326	Partial AVSD (= ostium primum ASD)	Dominant Sporadic	show hide Genetic evidence no parental DNA and data available; 0/400 normal controls in silico prediction The C4148T change results in a substitution of isoleucine for threonine at amino acid 311 (T311I) in the second cb-EGF domain. Functional studies Comments
c.4201C>T	p.329R>C	AVSD: isolated atrial component (primum ASD)	PMID:12632326	Partial AVSD (= ostium primum ASD)	Dominant Sporadic	show hide Genetic evidence mutation inherited from unaffected father; unaffected brother and sister carry identical variant; 0/400 normal controls in silico prediction The addition of a free cysteine residue to a cb-EGF domain is predicted to disrupt the disulfide-bonding pattern for that domain. Consequently, this mutation would be expected to interfere with protein folding. Functional studies To determine if the R329C substitution altered characteristics of CRELD1, Robinson SW et al., 2003 expressed the wild-type or mutant allele with a carboxyl-terminal FLAG-epitope tag in stably transfected HEK 293 cells and visualized the protein by western blot analysis. Mobility of the R329C mutant protein was slightly retarded, compared with that of wild-type CRELD1 on SDS-PAGE in the presence of reducing agents. The altered mobility is not due to exposure of additional N-glycosylation sites, neither to a change in B-hydroxylation. Comments Given the low penetrance observed in this family, it is probable that CRELD1 is an AVSD-susceptibility gene and that CRELD1 mutations increase the risk of developing a heart defect, rather than being directly causative.
c.4201C>T	p.329R>C	AVSD: atrial & ventricular components (complete)	PMID:17036335	complete AVSD associated with ASD type 2, PDA, tricuspid regurgitation and Down Syndrome	Dominant Sporadic	show hide Genetic evidence inherited from unaffected mother; 0/400 normal controls; 0/30 subjects with Down syndrome without CHD in silico prediction The addition of a free cysteine residue to a cb-EGF domain is predicted to disrupt the disulfide-bonding pattern for that domain. Consequently, this mutation would be expected to interfere with protein folding. Functional studies To determine if the R329C substitution altered characteristics of CRELD1, Robinson SW et al., 2003 expressed the wild-type or mutant allele with a carboxyl-terminal FLAG-epitope tag in stably transfected HEK 293 cells and visualized the protein by western blot analysis. Mobility of the R329C mutant protein was slightly retarded, compared with that of wild-type CRELD1 on SDS-PAGE in the presence of reducing agents.The altered mobility is not due to exposure of additional N-glycosylation sites, neither to a change in B-hydroxylation. Comments The severity of the heart defect was greater in the individual with Down syndrome, who had a complete AVSD and additional cardiac anomalies, compared to the affected euploid individual with an isolated partial AVSD, raising the possibility that trisomy 21 exacerbates the effect of the CRELD1 C329 allele.
c.1240G>A	p.414E>K	AVSD: atrial & ventricular components (complete)	PMID:17036335	Complete AVSD associated with tricuspid regurgitation and Down syndrome	Dominant Sporadic	show hide Genetic evidence de novo 0/400 normal controls; 0/30 subjects with Down syndrome without CHD in silico prediction The substitution of a lysine for a glutamic acid residue introduces a change in charge at a position that is highly conserved among mammals. Functional studies Comments CRELD1 may contribute to the pathogenesis of AVSD in the context of trisomy 21.

Representation of protein CRELD1

Heart expression domain of CRELD1

No specified expression domain for CRELD1

Add a new domain where gene CRELD1 is expressed

Associated CHDs found by automated text mining

AGeneApart Method

• Atrioventricular septal defect (06.06.00) (sig = 6.597)

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Heart defects