Molecular aspects of CRKL in heart development and human disease
Molecular aspects of CRKL in heart development and human disease
批准号:
9197022
负责人:
BERNICE E MORROW
金额:
$81.0万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-07-15 至 2020-06-30
关键词:
22q11 Deletion Syndrome22q11.2AccountingAdaptor Signaling ProteinAffectAnteriorAortic Valve StenosisBackBase PairingBiological AssayBoxingCRKL geneCandidate Disease GeneCardiacCell physiologyCellsCessation of lifeChromosomesClinicalCodeComplexCongenital Heart DefectsDNADataDefectDevelopmentDiGeorge SyndromeDiseaseEmbryoEndocardiumEtiologyEvaluationFocal Adhesion Kinase 1GenesGeneticGenetic Predisposition to DiseaseGenetic TranscriptionHeartHeart AbnormalitiesHeart ValvesHumanHuman GeneticsIn VitroIndividualIntracardiac abnormalitiesInvestigationMAP Kinase GeneMediatingMesenchymalMolecularMusMutant Strains MiceMutationNeural Crest CellOutcomePathway interactionsPatientsPersistent Truncus ArteriosusPharyngeal ApparatusPhenotypePopulationProcessRare DiseasesReceptor Protein-Tyrosine KinasesRegulatory ElementReportingResearchRiskSamplingSeptateShprintzen syndromeSignal PathwaySignal TransductionSystemTestingTetralogy of FallotTissuesUntranslated RNAValidationVariantVascular Endothelial Growth FactorsWorkbasecardiogenesiscohortcongenital heart disorderconotruncal anomaly face syndromedifferential expressiondisease heterogeneityembryo cultureexome sequencinggene functiongene interactiongenetic approachgenome sequencinghuman diseasein vitro Assayin vivoinsightloss of functionmalformationmiddle agemouse modelmutantnovelparacrineprobandprogramstranscription factortranscriptome sequencingwhole genome
中文摘要
摘要
英文摘要
ABSTRACT
One of the greatest challenges in human genetics is to understand the genetic basis of complex disorders,
such as congenital heart disease (CHD). Studies of rare diseases with known genetic etiologies such as the
22q11.2 deletion syndrome (DiGeorge/velo-cardio-facial syndrome), can pinpoint disease genes and
mechanisms. Approximately 65% of 22q11DS patients have a congenital heart defect, mostly affecting the
cardiac outflow tract (OFT). These range from mild to severe and include persistent truncus arteriosus and
tetralogy of Fallot, at the severe end. Although TBX1, encoding a T-box transcription factor has been the
strongest candidate gene for CHD on chromosome 22q11.2, patients with similar heart defects, but non-
overlapping deletions within this region have been identified. In these patients with atypical deletions, CRKL,
encoding a cytoplasmic adaptor to receptor tyrosine kinase signaling is deleted, but not TBX1. This implicates
CRKL as a true disease gene. Although there have been extensive studies of TBX1, CRKL is understudied
with respect to heart development. The neural crest cells are a critical cell population in the pharyngeal
apparatus needed for proper alignment of the cardiac OFT. We propose to explore neural crest cell functions
of Crkl by evaluating new upstream and downstream pathways in Aim 1. We will then delineate the subset that
is critical for OFT development as mediated by Tbx1 and Crkl. Crkl-/- mice die at E16.5, earlier than can be
expected based upon only having OFT defects. Our pathological investigation has found that Crkl-/- embryos
have OFT valve defects in addition to alignment malformations. OFT valve anomalies are highly relevant to
22q11DS, as 9% of patients have these defects. This is a newly recognized defect for which the molecular
mechanisms are not known. Based upon this, and the presence of similar defects in endocardial-specific null
mutant embryos, we hypothesize that Crkl is required in this tissue to form derivative OFT valves via VEGF-
MAPK and additional signaling pathways. Endocardial functions will be tested in Aim 2. This work is also
clinically important because middle-aged 22q11DS patients have now been reported to have sudden
unexplained death, unconnected to the well-known intracardiac malformations. This might be related to the
presence of aortic valve stenosis, which accounts for 6.6% of 22q11.2 deletion patients. To connect the mouse
work in Aims 1 and 2 back to the human patients, we will evaluate existing whole exome sequence (WES) from
the current largest cohort that we are aware, of >1,000, 22q11DS patients for mutations in CRKL interaction
network genes in Aim 3. Exploratory studies of non-coding sequences in the candidate genes will be
performed. Validation will be done using more DNA samples from 500 22q11DS subjects and from emerging
WES data on non-syndromic CHD patients. The synergy of mouse and human studies will offer rapid
discoveries for a deep understanding of the complex genetic etiology of CHD.
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