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.

• MeSH
• degenerace retiny * genetika   patologie   MeSH
• encefalokéla diagnóza   genetika   patologie   MeSH
• HEK293 buňky MeSH
• lidé MeSH
• mutace MeSH
• odchlípení sítnice * vrozené   genetika   MeSH
• p21 aktivované kinasy genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• p21 aktivované kinasy MeSH
• PAK2 protein, human MeSH Prohlížeč

The transition zone (TZ) of eukaryotic cilia and flagella is a structural intermediate between the basal body and the axoneme that regulates ciliary traffic. Mutations in genes encoding TZ proteins (TZPs) cause human inherited diseases (ciliopathies). Here, we use the trypanosome to identify TZ components and localize them to TZ subdomains, showing that the Bardet-Biedl syndrome complex (BBSome) is more distal in the TZ than the Meckel syndrome (MKS) complex. Several of the TZPs identified here have human orthologs. Functional analysis shows essential roles for TZPs in motility, in building the axoneme central pair apparatus and in flagellum biogenesis. Analysis using RNAi and HaloTag fusion protein approaches reveals that most TZPs (including the MKS ciliopathy complex) show long-term stable association with the TZ, whereas the BBSome is dynamic. We propose that some Bardet-Biedl syndrome and MKS pleiotropy may be caused by mutations that impact TZP complex dynamics.

• Klíčová slova
• BBSome, MKS/B9 complex, cilium/flagellum, transition zone, trypanosome,
• MeSH
• Bardetův-Biedlův syndrom genetika   metabolismus   MeSH
• bazální tělíska metabolismus   ultrastruktura   MeSH
• cilie genetika   metabolismus   MeSH
• ciliopatie genetika   metabolismus   MeSH
• cytoskelet metabolismus   ultrastruktura   MeSH
• encefalokéla genetika   metabolismus   MeSH
• flagella genetika   metabolismus   ultrastruktura   MeSH
• fluorescenční mikroskopie MeSH
• kompartmentace buňky MeSH
• lidé MeSH
• mutace MeSH
• polycystická choroba ledvin genetika   metabolismus   MeSH
• poruchy ciliární motility genetika   metabolismus   MeSH
• proteom genetika   metabolismus   MeSH
• protozoální proteiny genetika   metabolismus   MeSH
• retinopathia pigmentosa MeSH
• RNA interference MeSH
• transmisní elektronová mikroskopie MeSH
• Trypanosoma genetika   metabolismus   ultrastruktura   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Názvy látek
• proteom MeSH
• protozoální proteiny MeSH