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Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis.

Pagnamenta AT, Howard MF, Wisniewski E, Popitsch N, Knight SJ, Keays DA, Quaghebeur G, Cox H, Cox P, Balla T, Taylor JC, Kini U - Hum. Mol. Genet. (2015)

Bottom Line: Polymicrogyria (PMG) is a structural brain abnormality involving the cerebral cortex that results from impaired neuronal migration and although several genes have been implicated, many cases remain unsolved.In this study, exome sequencing in a family where three fetuses had all been diagnosed with PMG and cerebellar hypoplasia allowed us to identify regions of the genome for which both chromosomes were shared identical-by-descent, reducing the search space for causative variants to 8.6% of the genome.Our results emphasize the importance of phosphoinositide signalling in early brain development.

View Article: PubMed Central - PubMed

Affiliation: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

No MeSH data available.


Related in: MedlinePlus

Amino acid conservation and structural modelling. (A) Sequence alignment of human type III PI 4-kinases, PI 3-kinases and PI kinase-related kinases within their catalytic domains. Highly conserved residues are highlighted in yellow and those with conservative substitutions with blue. Residues conserved between at least some of the groups are highlighted with green. The affected aspartate residue is labelled by a red asterisk. (B) Sequence alignment of orthologues of PI4KA from different eukaryotes. (C) The structure of the ATP-binding pocket of PI4KB with the ATP competitive inhibitor, PIK93 based on 4D0L (33). Red and yellow colours represent the C- and N-terminal halves of the catalytic site, respectively, while light blue is the N-terminal helical domain. Green indicates the activation loop. The conserved Aspartate residue (D579) is coloured magenta. (D) Model of the catalytic domain of PI4KA with ATP bound form (29) showing very similar features.
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DDV117F3: Amino acid conservation and structural modelling. (A) Sequence alignment of human type III PI 4-kinases, PI 3-kinases and PI kinase-related kinases within their catalytic domains. Highly conserved residues are highlighted in yellow and those with conservative substitutions with blue. Residues conserved between at least some of the groups are highlighted with green. The affected aspartate residue is labelled by a red asterisk. (B) Sequence alignment of orthologues of PI4KA from different eukaryotes. (C) The structure of the ATP-binding pocket of PI4KB with the ATP competitive inhibitor, PIK93 based on 4D0L (33). Red and yellow colours represent the C- and N-terminal halves of the catalytic site, respectively, while light blue is the N-terminal helical domain. Green indicates the activation loop. The conserved Aspartate residue (D579) is coloured magenta. (D) Model of the catalytic domain of PI4KA with ATP bound form (29) showing very similar features.

Mentions: Sequence alignment of multiple PI4Ks and PI3Ks show that the Aspartic acid corresponding to the 1854 position in PI4KA is highly conserved among PI3Ks and type III PI4Ks and within PI4KA enzymes across evolution and even among the PI-kinase-related kinases (Fig. 3A and B) (29,30). Structural studies on PI 3- and 4-kinases (31–33) and modelling of the PI4KA catalytic domain (29) shows that while this residue does not make direct contact with the ATP molecule, it is critical to the proper folding of the ATP-binding pocket (Fig. 3C and D). Based on these findings, it was expected that a mutation at this position is not tolerated.Figure 3.


Germline recessive mutations in PI4KA are associated with perisylvian polymicrogyria, cerebellar hypoplasia and arthrogryposis.

Pagnamenta AT, Howard MF, Wisniewski E, Popitsch N, Knight SJ, Keays DA, Quaghebeur G, Cox H, Cox P, Balla T, Taylor JC, Kini U - Hum. Mol. Genet. (2015)

Amino acid conservation and structural modelling. (A) Sequence alignment of human type III PI 4-kinases, PI 3-kinases and PI kinase-related kinases within their catalytic domains. Highly conserved residues are highlighted in yellow and those with conservative substitutions with blue. Residues conserved between at least some of the groups are highlighted with green. The affected aspartate residue is labelled by a red asterisk. (B) Sequence alignment of orthologues of PI4KA from different eukaryotes. (C) The structure of the ATP-binding pocket of PI4KB with the ATP competitive inhibitor, PIK93 based on 4D0L (33). Red and yellow colours represent the C- and N-terminal halves of the catalytic site, respectively, while light blue is the N-terminal helical domain. Green indicates the activation loop. The conserved Aspartate residue (D579) is coloured magenta. (D) Model of the catalytic domain of PI4KA with ATP bound form (29) showing very similar features.
© Copyright Policy - creative-commons
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC4459391&req=5

DDV117F3: Amino acid conservation and structural modelling. (A) Sequence alignment of human type III PI 4-kinases, PI 3-kinases and PI kinase-related kinases within their catalytic domains. Highly conserved residues are highlighted in yellow and those with conservative substitutions with blue. Residues conserved between at least some of the groups are highlighted with green. The affected aspartate residue is labelled by a red asterisk. (B) Sequence alignment of orthologues of PI4KA from different eukaryotes. (C) The structure of the ATP-binding pocket of PI4KB with the ATP competitive inhibitor, PIK93 based on 4D0L (33). Red and yellow colours represent the C- and N-terminal halves of the catalytic site, respectively, while light blue is the N-terminal helical domain. Green indicates the activation loop. The conserved Aspartate residue (D579) is coloured magenta. (D) Model of the catalytic domain of PI4KA with ATP bound form (29) showing very similar features.
Mentions: Sequence alignment of multiple PI4Ks and PI3Ks show that the Aspartic acid corresponding to the 1854 position in PI4KA is highly conserved among PI3Ks and type III PI4Ks and within PI4KA enzymes across evolution and even among the PI-kinase-related kinases (Fig. 3A and B) (29,30). Structural studies on PI 3- and 4-kinases (31–33) and modelling of the PI4KA catalytic domain (29) shows that while this residue does not make direct contact with the ATP molecule, it is critical to the proper folding of the ATP-binding pocket (Fig. 3C and D). Based on these findings, it was expected that a mutation at this position is not tolerated.Figure 3.

Bottom Line: Polymicrogyria (PMG) is a structural brain abnormality involving the cerebral cortex that results from impaired neuronal migration and although several genes have been implicated, many cases remain unsolved.In this study, exome sequencing in a family where three fetuses had all been diagnosed with PMG and cerebellar hypoplasia allowed us to identify regions of the genome for which both chromosomes were shared identical-by-descent, reducing the search space for causative variants to 8.6% of the genome.Our results emphasize the importance of phosphoinositide signalling in early brain development.

View Article: PubMed Central - PubMed

Affiliation: National Institute for Health Research Biomedical Research Centre, Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford OX3 7BN, UK.

No MeSH data available.


Related in: MedlinePlus