Investigation of the genetic etiology of aslan type multiple pterygium syndrome

Aslan type multiple pterygium syndrome (ATMPS) [OMIM: 605203], a variant of multiple pterygium syndrome (MPS), is an autosomal recessive disorder and characterized by craniofacial cleft, limb malformations and severe popliteal pterygium. ATMPS has been described only in one patient and depending on the phenotypic similarities it was suggested that it might be the same disorder with Bartsocas-Papas syndrome (BPS). The causative genes for ATMPS and Bartsocas-Papas syndrome are still unknown. In this thesis it was aimed to identify the causative gene of the ATMPS.In this study, we evaluated the original ATMPS family in which the syndrome was described. In ATMPS family there are six affected individuals and only two of them are still alive. Genome-wide homozygosity mapping and subsequent fine mapping revealed co-segregation of 0.71 cM interval between SNPs rs2838045 and rs225444 on chromosome 21q22.3 with disease in family. Mutation screening of the candidate gene revealed a homozygous c.362T>A (p.Ile121Asn) mutation in RIPK4 gene encoding receptor interacting serine threonine kinase 4 which has a critical role in NF-?B induced epidermal development and keratinocyte differentiation. Mutation screening in a family which there was an affected individual suffering from Bartsocas-Papas syndrome revealed a missense mutation, c.551C>T (p.Thr184Ile), in RIPK4 gene.In conclusion, here we suggested that ATMPS might be the variant of Bartsocas-Papas syndrome and mutations in RIPK4 gene encoding receptor interacting serine threonine kinase 4 protein which has a critical function in embryonic development cause ATMPS and BPS.Keywords: Aslan Type Multiple Pterygium Syndrome, Bartsocas-Papas Syndrome, RIPK4, RIP, NF-?B