Dataset Information

A mutation in mouse Pak1ip1 causes orofacial clefting while human PAK1IP1 maps to 6p24 translocation breaking points associated with orofacial clefting.

ABSTRACT: Orofacial clefts are among the most common birth defects and result in an improper formation of the mouth or the roof of the mouth. Monosomy of the distal aspect of human chromosome 6p has been recognized as causative in congenital malformations affecting the brain and cranial skeleton including orofacial clefts. Among the genes located in this region is PAK1IP1, which encodes a nucleolar factor involved in ribosomal stress response. Here, we report the identification of a novel mouse line that carries a point mutation in the Pak1ip1 gene. Homozygous mutants show severe developmental defects of the brain and craniofacial skeleton, including a median orofacial cleft. We recovered this line of mice in a forward genetic screen and named the allele manta-ray (mray). Our findings prompted us to examine human cases of orofacial clefting for mutations in the PAK1IP1 gene or association with the locus. No deleterious variants in the PAK1IP1 gene coding region were recognized, however, we identified a borderline association effect for SNP rs494723 suggesting a possible role for the PAK1IP1 gene in human orofacial clefting.

SUBMITTER: Ross AP

PROVIDER: S-EPMC3723895 | biostudies-literature | 2013

REPOSITORIES: biostudies-literature

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A mutation in mouse Pak1ip1 causes orofacial clefting while human PAK1IP1 maps to 6p24 translocation breaking points associated with orofacial clefting.

Ross Adam P AP Mansilla M Adela MA Choe Youngshik Y Helminski Simon S Sturm Richard R Maute Roy L RL May Scott R SR Hozyasz Kamil K KK Wójcicki Piotr P Mostowska Adrianna A Davidson Beth B Adamopoulos Iannis E IE Pleasure Samuel J SJ Murray Jeffrey C JC Zarbalis Konstantinos S KS

PloS one 20130725 7

Orofacial clefts are among the most common birth defects and result in an improper formation of the mouth or the roof of the mouth. Monosomy of the distal aspect of human chromosome 6p has been recognized as causative in congenital malformations affecting the brain and cranial skeleton including orofacial clefts. Among the genes located in this region is PAK1IP1, which encodes a nucleolar factor involved in ribosomal stress response. Here, we report the identification of a novel mouse line that ...[more]

PMID: 23935987

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Project description:Although children with oral clefts have a higher risk for dental anomalies when compared with the general population, prior studies have shown conflicting results regarding their dental decay risk. Also, few studies have assessed dental decay risk in unaffected relatives of children with clefts. Thus, the question of increased risk of dental decay in individuals with oral clefts or their unaffected relatives is still open for empirical investigation. This study characterizes dental decay in the largest international cohort to date of children with nonsyndromic clefts and their relatives, as compared with controls, and it addresses whether families with oral clefts have a significantly increased risk for dental decay versus the general population. A total of 3,326 subjects were included: 639 case probands, 1,549 unaffected relatives, and 1,138 controls. Decay was identified from in-person dental examinations or intraoral photographs. Case-control differences were tested with regression analysis. No significant differences were shown in percentage decayed and filled teeth and decayed teeth in the primary dentition (dft, dt) and permanent dentition (DFT, DT) in cases versus controls. In the cleft region, no significant differences were seen in primary or permanent decay (dt, DT) when compared with controls. No difference was found with regard to cleft type and percentage dft, dt, DFT, and DT in case probands. Nonsignificant differences were found in unaffected siblings and parents versus controls (primary and permanent dentitions). Collectively, these findings indicate that individuals with nonsyndromic oral clefts and their families do not have a higher dental decay risk as compared with the general population. These results suggest that either genetic or environmental factors underlying a higher susceptibility for dental anomalies do not increase caries risk or that the seemingly higher risk for dental decay associated with increased dental anomalies in case probands may be superseded by possible greater access to dental care.

Project description:Children with oral clefts show a wide range of dental anomalies, adding complexity to understanding the phenotypic spectrum of orofacial clefting. The evidence is mixed, however, on whether the prevalence of dental anomalies is elevated in unaffected relatives and is mostly based on small samples. In the largest international cohort to date of children with nonsyndromic clefts, their relatives, and controls, this study characterizes the spectrum of cleft-related dental anomalies and evaluates whether families with clefting have a significantly higher risk for such anomalies compared with the general population. A total of 3,811 individuals were included: 660 cases with clefts, 1,922 unaffected relatives, and 1,229 controls. Dental anomalies were identified from in-person dental exams or intraoral photographs, and case-control differences were tested using χ(2) statistics. Cases had higher rates of dental anomalies in the maxillary arch than did controls for primary (21% vs. 4%, P = 3 × 10(-8)) and permanent dentitions (51% vs. 8%, P = 4 × 10(-62)) but not in the mandible. Dental anomalies were more prevalent in cleft lip with cleft palate than other cleft types. More anomalies were seen in the ipsilateral side of the cleft. Agenesis and tooth displacements were the most common dental anomalies found in case probands for primary and permanent dentitions. Compared with controls, unaffected siblings (10% vs. 2%, P = 0.003) and parents (13% vs. 7%, P = 0.001) showed a trend for increased anomalies of the maxillary permanent dentition. Yet, these differences were nonsignificant after multiple-testing correction, suggesting genetic heterogeneity in some families carrying susceptibility to both overt clefts and dental anomalies. Collectively, the findings suggest that most affected families do not have higher genetic risk for dental anomalies than the general population and that the higher prevalence of anomalies in cases is primarily a physical consequence of the cleft and surgical interventions.

Dataset Information

A mutation in mouse Pak1ip1 causes orofacial clefting while human PAK1IP1 maps to 6p24 translocation breaking points associated with orofacial clefting.

Publications

A mutation in mouse Pak1ip1 causes orofacial clefting while human PAK1IP1 maps to 6p24 translocation breaking points associated with orofacial clefting.

Similar Datasets

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