Limits...
Regulatory variant in FZD6 gene contributes to nonsyndromic cleft lip and palate in an African-American family.

Cvjetkovic N, Maili L, Weymouth KS, Hashmi SS, Mulliken JB, Topczewski J, Letra A, Yuan Q, Blanton SH, Swindell EC, Hecht JT - Mol Genet Genomic Med (2015)

Bottom Line: The variant C allele segregated with NSCLP in this family, through affected and unaffected individuals, and was found in one other NSCLP African-American family.Functional assays showed that this allele creates an allele-specific protein-binding site and decreases promoter activity.We hypothesize, therefore, that alteration in FZD6 expression contributes to NSCLP in this family by perturbing the WNT signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Texas Medical School at Houston Houston, Texas ; Graduate School of Biomedical Sciences, University of Texas Health Science Center Houston, Texas.

ABSTRACT
Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect affecting 135,000 newborns worldwide each year. While a multifactorial etiology has been suggested as the cause, despite decades of research, the genetic underpinnings of NSCLP remain largely unexplained. In our previous genome-wide linkage study of a large NSCLP African-American family, we identified a candidate locus at 8q21.3-24.12 (LOD = 2.98). This region contained four genes, Frizzled-6 (FZD6), Matrilin-2 (MATN2), Odd-skipped related 2 (OSR2) and Solute Carrier Family 25, Member 32 (SLC25A32). FZD6 was located under the maximum linkage peak. In this study, we sequenced the coding and noncoding regions of these genes in two affected family members, and identified a rare variant in intron 1 of FZD6 (rs138557689; c.-153 + 432A>C). The variant C allele segregated with NSCLP in this family, through affected and unaffected individuals, and was found in one other NSCLP African-American family. Functional assays showed that this allele creates an allele-specific protein-binding site and decreases promoter activity. We also observed that loss and gain of fzd6 in zebrafish contributes to craniofacial anomalies. FZD6 regulates the WNT signaling pathway, which is involved in craniofacial development, including midfacial formation and upper labial fusion. We hypothesize, therefore, that alteration in FZD6 expression contributes to NSCLP in this family by perturbing the WNT signaling pathway.

No MeSH data available.


Related in: MedlinePlus

Multiplex NSCLP African-American family. Pedigree depicts eleven individuals with NSCLP spanning three generations. Filled symbols denote affected individuals and asterisks (*) denote individuals included in the genome scan reported by Chiquet et al. (2009). Laterality is indicated as B for bilateral and U for unilateral. All of the examined individuals had cleft lip with cleft palate. C allele of rs138557689 segregates with affected individuals and is transmitted by four unaffected individuals originating from individual I-3. C allele is also present in 5 additional unaffected individuals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4585452&req=5

fig01: Multiplex NSCLP African-American family. Pedigree depicts eleven individuals with NSCLP spanning three generations. Filled symbols denote affected individuals and asterisks (*) denote individuals included in the genome scan reported by Chiquet et al. (2009). Laterality is indicated as B for bilateral and U for unilateral. All of the examined individuals had cleft lip with cleft palate. C allele of rs138557689 segregates with affected individuals and is transmitted by four unaffected individuals originating from individual I-3. C allele is also present in 5 additional unaffected individuals.

Mentions: As part of our NSCLP gene studies, we ascertained a large multiplex African-American family with 11 cases of NSCLP segregating in 3 generations (Fig.1). This family is unique because NSCLP is less common in African-American populations. We previously reported suggestive evidence for linkage in this family under a dominant model with reduced penetrance (penetrances of 0.24 and 0.32 in females and males, respectively; phenocopy rate of 0.001) (Chiquet et al. 2009) to the 8q21.3-24.12 region (LOD = 2.98, maximum possible LOD) flanked by rs150615 and rs2034844 (chr8: 90638305-121,344,027). This was the only region shared by all affected individuals. In other unpublished studies, there was no evidence for structural variation segregating with the phenotype in the family. A meta-analysis of 13 NSCLP genome scans previously reported association to the 8q24.21 region (Marazita et al. 2002). The 8q24.21-associated region is defined by rs3857888-rs17821251 (chr8:129894043-130078415) and does not overlap with our linkage region (8 Mb away). Inspection of the linkage region identified four candidate genes: Frizzled-6 (FZD6), Matrilin-2 (MATN2), Odd-Skipped Related 2 (OSR2), and Solute Carrier Family 25 Member 32 (SLC25A32). Herein, we report the identification of a rare intronic variant in FZD6 that segregates with the phenotype and creates a novel allele-specific protein-binding site that decreases promoter activity.


Regulatory variant in FZD6 gene contributes to nonsyndromic cleft lip and palate in an African-American family.

Cvjetkovic N, Maili L, Weymouth KS, Hashmi SS, Mulliken JB, Topczewski J, Letra A, Yuan Q, Blanton SH, Swindell EC, Hecht JT - Mol Genet Genomic Med (2015)

Multiplex NSCLP African-American family. Pedigree depicts eleven individuals with NSCLP spanning three generations. Filled symbols denote affected individuals and asterisks (*) denote individuals included in the genome scan reported by Chiquet et al. (2009). Laterality is indicated as B for bilateral and U for unilateral. All of the examined individuals had cleft lip with cleft palate. C allele of rs138557689 segregates with affected individuals and is transmitted by four unaffected individuals originating from individual I-3. C allele is also present in 5 additional unaffected individuals.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4585452&req=5

fig01: Multiplex NSCLP African-American family. Pedigree depicts eleven individuals with NSCLP spanning three generations. Filled symbols denote affected individuals and asterisks (*) denote individuals included in the genome scan reported by Chiquet et al. (2009). Laterality is indicated as B for bilateral and U for unilateral. All of the examined individuals had cleft lip with cleft palate. C allele of rs138557689 segregates with affected individuals and is transmitted by four unaffected individuals originating from individual I-3. C allele is also present in 5 additional unaffected individuals.
Mentions: As part of our NSCLP gene studies, we ascertained a large multiplex African-American family with 11 cases of NSCLP segregating in 3 generations (Fig.1). This family is unique because NSCLP is less common in African-American populations. We previously reported suggestive evidence for linkage in this family under a dominant model with reduced penetrance (penetrances of 0.24 and 0.32 in females and males, respectively; phenocopy rate of 0.001) (Chiquet et al. 2009) to the 8q21.3-24.12 region (LOD = 2.98, maximum possible LOD) flanked by rs150615 and rs2034844 (chr8: 90638305-121,344,027). This was the only region shared by all affected individuals. In other unpublished studies, there was no evidence for structural variation segregating with the phenotype in the family. A meta-analysis of 13 NSCLP genome scans previously reported association to the 8q24.21 region (Marazita et al. 2002). The 8q24.21-associated region is defined by rs3857888-rs17821251 (chr8:129894043-130078415) and does not overlap with our linkage region (8 Mb away). Inspection of the linkage region identified four candidate genes: Frizzled-6 (FZD6), Matrilin-2 (MATN2), Odd-Skipped Related 2 (OSR2), and Solute Carrier Family 25 Member 32 (SLC25A32). Herein, we report the identification of a rare intronic variant in FZD6 that segregates with the phenotype and creates a novel allele-specific protein-binding site that decreases promoter activity.

Bottom Line: The variant C allele segregated with NSCLP in this family, through affected and unaffected individuals, and was found in one other NSCLP African-American family.Functional assays showed that this allele creates an allele-specific protein-binding site and decreases promoter activity.We hypothesize, therefore, that alteration in FZD6 expression contributes to NSCLP in this family by perturbing the WNT signaling pathway.

View Article: PubMed Central - PubMed

Affiliation: Department of Pediatrics, University of Texas Medical School at Houston Houston, Texas ; Graduate School of Biomedical Sciences, University of Texas Health Science Center Houston, Texas.

ABSTRACT
Nonsyndromic cleft lip with or without cleft palate (NSCLP) is a common birth defect affecting 135,000 newborns worldwide each year. While a multifactorial etiology has been suggested as the cause, despite decades of research, the genetic underpinnings of NSCLP remain largely unexplained. In our previous genome-wide linkage study of a large NSCLP African-American family, we identified a candidate locus at 8q21.3-24.12 (LOD = 2.98). This region contained four genes, Frizzled-6 (FZD6), Matrilin-2 (MATN2), Odd-skipped related 2 (OSR2) and Solute Carrier Family 25, Member 32 (SLC25A32). FZD6 was located under the maximum linkage peak. In this study, we sequenced the coding and noncoding regions of these genes in two affected family members, and identified a rare variant in intron 1 of FZD6 (rs138557689; c.-153 + 432A>C). The variant C allele segregated with NSCLP in this family, through affected and unaffected individuals, and was found in one other NSCLP African-American family. Functional assays showed that this allele creates an allele-specific protein-binding site and decreases promoter activity. We also observed that loss and gain of fzd6 in zebrafish contributes to craniofacial anomalies. FZD6 regulates the WNT signaling pathway, which is involved in craniofacial development, including midfacial formation and upper labial fusion. We hypothesize, therefore, that alteration in FZD6 expression contributes to NSCLP in this family by perturbing the WNT signaling pathway.

No MeSH data available.


Related in: MedlinePlus