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Článek

Dominant monoallelic variant in the PAK2 gene causes Knobloch syndrome type 2

Antonarakis, Stylianos E
Autor Autorita ORCID Department of Genetic Medicine and Development, University of Geneva Medical Faculty, Geneva 1211, Switzerland iGE3 Institute of Genetics and Genomics of Geneva, Geneva 1211, Switzerland
Holoubek, Aleš
Autor Holoubek, Aleš Department of Proteomics, Institute of Hematology and Blood Transfusion, Prague 12820, Czech Republic
Rapti, Melivoia
Autor Rapti, Melivoia Department of Endocrinology Diabetes and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland
Rademaker, Jesse
Autor Rademaker, Jesse Department of Endocrinology Diabetes and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland
Meylan, Jenny
Autor Meylan, Jenny Department of Endocrinology Diabetes and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland
Iwaszkiewicz, Justyna
Autor Iwaszkiewicz, Justyna ORCID Molecular Modeling Group, Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland
Zoete, Vincent
Autor Zoete, Vincent ORCID Molecular Modeling Group, Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland Department of Fundamental Oncology, Ludwig Institute for Cancer Research, Lausanne University, Epalinges 1066, Switzerland
Wilson, Callum
Autor Wilson, Callum ORCID National Metabolic Service, Starship Children's Hospital, Auckland 1142, New Zealand
Taylor, Juliet
Autor Taylor, Juliet Genetic Health Services New Zealand - Northern Hub, Auckland City Hospital, Auckland 1142, New Zealand
Ansar, Muhammad
Autor Ansar, Muhammad ORCID Institute of Molecular and Clinical Ophtalmology Basel (IOB), Basel 4031, Switzerland

Human molecular genetics. 2021 ; 31 (1) : 1-9. [pub] 20211217

Hum Mol Genet
ISSN 1460-2083
Medvik
Zdroj

Knobloch syndrome is an autosomal recessive phenotype mainly characterized by retinal detachment and encephalocele caused by biallelic pathogenic variants in the COL18A1 gene. However, there are patients clinically diagnosed as Knobloch syndrome with unknown molecular etiology not linked to COL18A1. We studied an historical pedigree (published in 1998) designated as KNO2 (Knobloch type 2 syndrome with intellectual disability, autistic behavior, retinal degeneration, encephalocele). Whole exome sequencing of the two affected siblings and the normal parents resulted in the identification of a PAK2 non-synonymous substitution p.(Glu435Lys) as a causative variant. The variant was monoallelic and apparently de novo in both siblings indicating a likely germ-line mosaicism in one of the parents; the mosaicism, however, could not be observed after deep sequencing of blood parental DNA. PAK2 encodes a member of a small group of serine/threonine kinases; these P21-activating kinases (PAKs) are essential in signal transduction and cellular regulation (cytoskeletal dynamics, cell motility, death and survival signaling and cell cycle progression). Structural analysis of the PAK2 p.(Glu435Lys) variant that is located in the kinase domain of the protein predicts a possible compromise in the kinase activity. Functional analysis of the p.(Glu435Lys) PAK2 variant in transfected HEK293T cells results in a partial loss of the kinase activity. PAK2 has been previously suggested as an autism-related gene. Our results show that PAK2-induced phenotypic spectrum is broad and not fully understood. We conclude that the KNO2 syndrome in the studied family is dominant and caused by a deleterious variant in the PAK2 gene.