Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies
Glycosylphosphatidylinositol (GPI)-anchored proteins are ubiquitously expressed in the human body and are important for various functions at the cell surface. Mutations in many GPI biosynthesis genes have been described to date in patients with multi-system disease and together these constitute a su...
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| Format: | Online |
| Language: | English |
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Oxford University Press
2015
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| Online Access: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599673/ |
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pubmed-45996732015-10-14 Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies Ilkovski, Biljana Pagnamenta, Alistair T. O'Grady, Gina L. Kinoshita, Taroh Howard, Malcolm F. Lek, Monkol Thomas, Brett Turner, Anne Christodoulou, John Sillence, David Knight, Samantha J.L. Popitsch, Niko Keays, David A. Anzilotti, Consuelo Goriely, Anne Waddell, Leigh B. Brilot, Fabienne North, Kathryn N. Kanzawa, Noriyuki Macarthur, Daniel G. Taylor, Jenny C. Kini, Usha Murakami, Yoshiko Clarke, Nigel F. Articles Glycosylphosphatidylinositol (GPI)-anchored proteins are ubiquitously expressed in the human body and are important for various functions at the cell surface. Mutations in many GPI biosynthesis genes have been described to date in patients with multi-system disease and together these constitute a subtype of congenital disorders of glycosylation. We used whole exome sequencing in two families to investigate the genetic basis of disease and used RNA and cellular studies to investigate the functional consequences of sequence variants in the PIGY gene. Two families with different phenotypes had homozygous recessive sequence variants in the GPI biosynthesis gene PIGY. Two sisters with c.137T>C (p.Leu46Pro) PIGY variants had multi-system disease including dysmorphism, seizures, severe developmental delay, cataracts and early death. There were significantly reduced levels of GPI-anchored proteins (CD55 and CD59) on the surface of patient-derived skin fibroblasts (∼20–50% compared with controls). In a second, consanguineous family, two siblings had moderate development delay and microcephaly. A homozygous PIGY promoter variant (c.-540G>A) was detected within a 7.7 Mb region of autozygosity. This variant was predicted to disrupt a SP1 consensus binding site and was shown to be associated with reduced gene expression. Mutations in PIGY can occur in coding and non-coding regions of the gene and cause variable phenotypes. This article contributes to understanding of the range of disease phenotypes and disease genes associated with deficiencies of the GPI-anchor biosynthesis pathway and also serves to highlight the potential importance of analysing variants detected in 5′-UTR regions despite their typically low coverage in exome data. Oxford University Press 2015-11-01 2015-08-20 /pmc/articles/PMC4599673/ /pubmed/26293662 http://dx.doi.org/10.1093/hmg/ddv331 Text en © The Author 2015. Published by Oxford University Press http://creativecommons.org/licenses/by/4.0/ This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted reuse, distribution, and reproduction in any medium, provided the original work is properly cited. |
| repository_type |
Open Access Journal |
| institution_category |
Foreign Institution |
| institution |
US National Center for Biotechnology Information |
| building |
NCBI PubMed |
| collection |
Online Access |
| language |
English |
| format |
Online |
| author |
Ilkovski, Biljana Pagnamenta, Alistair T. O'Grady, Gina L. Kinoshita, Taroh Howard, Malcolm F. Lek, Monkol Thomas, Brett Turner, Anne Christodoulou, John Sillence, David Knight, Samantha J.L. Popitsch, Niko Keays, David A. Anzilotti, Consuelo Goriely, Anne Waddell, Leigh B. Brilot, Fabienne North, Kathryn N. Kanzawa, Noriyuki Macarthur, Daniel G. Taylor, Jenny C. Kini, Usha Murakami, Yoshiko Clarke, Nigel F. |
| spellingShingle |
Ilkovski, Biljana Pagnamenta, Alistair T. O'Grady, Gina L. Kinoshita, Taroh Howard, Malcolm F. Lek, Monkol Thomas, Brett Turner, Anne Christodoulou, John Sillence, David Knight, Samantha J.L. Popitsch, Niko Keays, David A. Anzilotti, Consuelo Goriely, Anne Waddell, Leigh B. Brilot, Fabienne North, Kathryn N. Kanzawa, Noriyuki Macarthur, Daniel G. Taylor, Jenny C. Kini, Usha Murakami, Yoshiko Clarke, Nigel F. Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies |
| author_facet |
Ilkovski, Biljana Pagnamenta, Alistair T. O'Grady, Gina L. Kinoshita, Taroh Howard, Malcolm F. Lek, Monkol Thomas, Brett Turner, Anne Christodoulou, John Sillence, David Knight, Samantha J.L. Popitsch, Niko Keays, David A. Anzilotti, Consuelo Goriely, Anne Waddell, Leigh B. Brilot, Fabienne North, Kathryn N. Kanzawa, Noriyuki Macarthur, Daniel G. Taylor, Jenny C. Kini, Usha Murakami, Yoshiko Clarke, Nigel F. |
| author_sort |
Ilkovski, Biljana |
| title |
Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies |
| title_short |
Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies |
| title_full |
Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies |
| title_fullStr |
Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies |
| title_full_unstemmed |
Mutations in PIGY: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies |
| title_sort |
mutations in pigy: expanding the phenotype of inherited glycosylphosphatidylinositol deficiencies |
| description |
Glycosylphosphatidylinositol (GPI)-anchored proteins are ubiquitously expressed in the human body and are important for various functions at the cell surface. Mutations in many GPI biosynthesis genes have been described to date in patients with multi-system disease and together these constitute a subtype of congenital disorders of glycosylation. We used whole exome sequencing in two families to investigate the genetic basis of disease and used RNA and cellular studies to investigate the functional consequences of sequence variants in the PIGY gene. Two families with different phenotypes had homozygous recessive sequence variants in the GPI biosynthesis gene PIGY. Two sisters with c.137T>C (p.Leu46Pro) PIGY variants had multi-system disease including dysmorphism, seizures, severe developmental delay, cataracts and early death. There were significantly reduced levels of GPI-anchored proteins (CD55 and CD59) on the surface of patient-derived skin fibroblasts (∼20–50% compared with controls). In a second, consanguineous family, two siblings had moderate development delay and microcephaly. A homozygous PIGY promoter variant (c.-540G>A) was detected within a 7.7 Mb region of autozygosity. This variant was predicted to disrupt a SP1 consensus binding site and was shown to be associated with reduced gene expression. Mutations in PIGY can occur in coding and non-coding regions of the gene and cause variable phenotypes. This article contributes to understanding of the range of disease phenotypes and disease genes associated with deficiencies of the GPI-anchor biosynthesis pathway and also serves to highlight the potential importance of analysing variants detected in 5′-UTR regions despite their typically low coverage in exome data. |
| publisher |
Oxford University Press |
| publishDate |
2015 |
| url |
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4599673/ |
| _version_ |
1613485877280899072 |