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Research > Portfolio > Funded Research

From left to right:

Anne Bowcock, Ph.D., Dept of  Oncological Sciences, Dermatology and Genetics and Genome Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA

Amy Paller, M.D., M.S., Professor and Chair, Dermatology, Northwestern University, Chicago, IL, USA

Marieke Seyger, Ph.D., Medical Researcher at Radboud University Medical Center, Nijmegen, Netherlands

 

Discovery Grant
2018

Genetic Analysis of Pediatric Psoriasis

Psoriasis
Active

Layman's Statement: The underlying basis for most human diseases, including psoriasis, includes a genetic component, and its discovery may be critical to the development of novel treatments. We hypothesize that severe pediatric psoriasis is more likely than adult psoriasis to result from single gene mutations that have arisen spontaneously and, thus, are not present in either parent. We have identified such a gene (CARD14) where approximately 20% of severe pediatric cases with CARD14 alterations harbor de novo mutations and hypothesize that similar genes can be identified with state-of-the-art genetic approaches. By analyzing 30 children with moderate-to-severe pediatric psoriasis, with no immediate family history of disease, we will identify those with CARD14 mutations and will then look for additional spontaneous mutations in other genes that are likely to lead to psoriasis. We will then examine these genes in a further 300 children with moderate-to-severe psoriasis. This approach will provide further insights into the reason for the development of psoriasis in children, and may highlight new ways to combat it. In the future, we anticipate extending these genetic investigations through engaging the Psoriasis Investigator Group (PsIG) of PeDRA as co-investigators in order to screen a larger pediatric psoriasis cohort. 


Grant Abstract: A few years ago, we identified rare highly penetrant damaging mutations in the caspase recruitment domain 14 protein (CARD14) gene that lead to both adult and pediatric psoriasis. One child with severe psoriasis with no family history of psoriasis harbored a de novo mutation in CARD14 (p.E138A) that had arisen in the germline of one of her parents. This child did not respond to any conventional psoriasis treatments, but did respond well to the anti p40 inhibitor ustekinumab. We showed that pathogenic CARD14 mutations lead to enhanced levels of NFkB activation by keratinocytes in an ex vivo assay, and proposed a model where this leads to upregulation of genes encoding the IL23 subunits (p40 and p19) by dendritic cells. We have now sequenced CARD14 coding exons in a cohort of more than 260 pediatric psoriasis cases from the Netherlands and have identified five individuals with potentially deleterious and rare variants in CARD14, including the familial p.G117S CARD14 mutation. We now plan to examine the effect of these novel CARD14 mutations on NF-kB levels, since this will indicate which are likely to lead to psoriasis. We also hypothesize that there are additional rare dominantly acting mutations that have arisen de novo in novel genes in pediatric cases with moderate-to-severe psoriasis and no immediate family history of psoriasis. We will seek CARD14 mutations in 30 trios, each consisting of a moderate-to-severe pediatric case requiring systemic intervention and unaffected parents (to facilitate finding de novo gene changes). We will then perform exome sequencing on 20 of the trios without a pathogenic CARD14 mutation. We expect that this will reveal 2-3 mutations per exome in the child, but not a parent, and that some of these de novo changes in novel genes could lead to psoriasis. We will then re-sequence coding exons of ten of these genes in a Dutch pediatric cohort of 300 cases to obtain further genetic evidence for their role in psoriasis. As detailed clinical information of all children of this cohort are captured in the ChildCAPTURE registry findings can be correlated with their clinical characteristics and treatment response.