Detail
Článek
Článek online
FT
Medvik - BMČ
  • Je něco špatně v tomto záznamu ?

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

SE. Antonarakis, A. Holoubek, M. Rapti, J. Rademaker, J. Meylan, J. Iwaszkiewicz, V. Zoete, C. Wilson, J. Taylor, M. Ansar, C. Borel, O. Menzel, K. Kuželová, FA. Santoni

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

Jazyk angličtina Země Velká Británie

Typ dokumentu časopisecké články, práce podpořená grantem

Perzistentní odkaz   https://www.medvik.cz/link/bmc22019600

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.

Citace poskytuje Crossref.org

000      
00000naa a2200000 a 4500
001      
bmc22019600
003      
CZ-PrNML
005      
20220804135817.0
007      
ta
008      
220720s2021 xxk f 000 0|eng||
009      
AR
024    7_
$a 10.1093/hmg/ddab026 $2 doi
035    __
$a (PubMed)33693784
040    __
$a ABA008 $b cze $d ABA008 $e AACR2
041    0_
$a eng
044    __
$a xxk
100    1_
$a Antonarakis, Stylianos E $u Department of Genetic Medicine and Development, University of Geneva Medical Faculty, Geneva 1211, Switzerland $u iGE3 Institute of Genetics and Genomics of Geneva, Geneva 1211, Switzerland $1 https://orcid.org/0000000189075823 $7 mub2010600083
245    10
$a Dominant monoallelic variant in the PAK2 gene causes Knobloch syndrome type 2 / $c SE. Antonarakis, A. Holoubek, M. Rapti, J. Rademaker, J. Meylan, J. Iwaszkiewicz, V. Zoete, C. Wilson, J. Taylor, M. Ansar, C. Borel, O. Menzel, K. Kuželová, FA. Santoni
520    9_
$a 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.
650    _2
$a encefalokéla $x diagnóza $x genetika $x patologie $7 D004677
650    _2
$a HEK293 buňky $7 D057809
650    _2
$a lidé $7 D006801
650    _2
$a mutace $7 D009154
650    12
$a degenerace retiny $x genetika $x patologie $7 D012162
650    12
$a odchlípení sítnice $x vrozené $x genetika $7 D012163
650    _2
$a p21 aktivované kinasy $x genetika $7 D054462
655    _2
$a časopisecké články $7 D016428
655    _2
$a práce podpořená grantem $7 D013485
700    1_
$a Holoubek, Aleš $u Department of Proteomics, Institute of Hematology and Blood Transfusion, Prague 12820, Czech Republic
700    1_
$a Rapti, Melivoia $u Department of Endocrinology Diabetes and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland
700    1_
$a Rademaker, Jesse $u Department of Endocrinology Diabetes and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland
700    1_
$a Meylan, Jenny $u Department of Endocrinology Diabetes and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland
700    1_
$a Iwaszkiewicz, Justyna $u Molecular Modeling Group, Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland $1 https://orcid.org/000000033494589X
700    1_
$a Zoete, Vincent $u Molecular Modeling Group, Swiss Institute of Bioinformatics, Lausanne 1015, Switzerland $u Department of Fundamental Oncology, Ludwig Institute for Cancer Research, Lausanne University, Epalinges 1066, Switzerland $1 https://orcid.org/0000000223366537
700    1_
$a Wilson, Callum $u National Metabolic Service, Starship Children's Hospital, Auckland 1142, New Zealand $1 https://orcid.org/000000032034767X
700    1_
$a Taylor, Juliet $u Genetic Health Services New Zealand - Northern Hub, Auckland City Hospital, Auckland 1142, New Zealand
700    1_
$a Ansar, Muhammad $u Institute of Molecular and Clinical Ophtalmology Basel (IOB), Basel 4031, Switzerland $1 https://orcid.org/0000000172993185
700    1_
$a Borel, Christelle $u Department of Genetic Medicine and Development, University of Geneva Medical Faculty, Geneva 1211, Switzerland $1 https://orcid.org/0000000275259418
700    1_
$a Menzel, Olivier $u Health 2030 Genome Center, Foundation Campus Biotech Geneva Foundation, Geneva 1202, Switzerland $1 https://orcid.org/0000000335023264
700    1_
$a Kuželová, Kateřina $u Department of Proteomics, Institute of Hematology and Blood Transfusion, Prague 12820, Czech Republic $1 https://orcid.org/0000000296286255 $7 xx0115456
700    1_
$a Santoni, Federico A $u Department of Endocrinology Diabetes and Metabolism, Lausanne University Hospital, Lausanne 1011, Switzerland $u Faculty of Biology and Medicine, University of Lausanne, Lausanne 1011, Switzerland $1 https://orcid.org/0000000232584747
773    0_
$w MED00002077 $t Human molecular genetics $x 1460-2083 $g Roč. 31, č. 1 (2021), s. 1-9
856    41
$u https://pubmed.ncbi.nlm.nih.gov/33693784 $y Pubmed
910    __
$a ABA008 $b sig $c sign $y p $z 0
990    __
$a 20220720 $b ABA008
991    __
$a 20220804135810 $b ABA008
999    __
$a ok $b bmc $g 1822989 $s 1170843
BAS    __
$a 3
BAS    __
$a PreBMC
BMC    __
$a 2021 $b 31 $c 1 $d 1-9 $e 20211217 $i 1460-2083 $m Human molecular genetics $n Hum Mol Genet $x MED00002077
LZP    __
$a Pubmed-20220720

Najít záznam

Citační ukazatele

Možnosti archivace