Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia

Details

Serval ID
serval:BIB_26981FA4B21E
Type
Article: article from journal or magazin.
Collection
Publications
Institution
Title
Pathogenic Variants in PIGG Cause Intellectual Disability with Seizures and Hypotonia
Journal
Am J Hum Genet
Author(s)
Makrythanasis P., Kato M., Zaki M. S., Saitsu H., Nakamura K., Santoni F. A., Miyatake S., Nakashima M., Issa M. Y., Guipponi M., Letourneau A., Logan C. V., Roberts N., Parry D. A., Johnson C. A., Matsumoto N., Hamamy H., Sheridan E., Kinoshita T., Antonarakis S. E., Murakami Y.
ISSN
1537-6605 (Electronic)
ISSN-L
0002-9297
Publication state
Published
Issued date
2016
Volume
98
Number
4
Pages
615-26
Language
english
Notes
Makrythanasis, Periklis
Kato, Mitsuhiro
Zaki, Maha S
Saitsu, Hirotomo
Nakamura, Kazuyuki
Santoni, Federico A
Miyatake, Satoko
Nakashima, Mitsuko
Issa, Mahmoud Y
Guipponi, Michel
Letourneau, Audrey
Logan, Clare V
Roberts, Nicola
Parry, David A
Johnson, Colin A
Matsumoto, Naomichi
Hamamy, Hanan
Sheridan, Eamonn
Kinoshita, Taroh
Antonarakis, Stylianos E
Murakami, Yoshiko
eng
Research Support, Non-U.S. Gov't
Am J Hum Genet. 2016 Apr 7;98(4):615-26. doi: 10.1016/j.ajhg.2016.02.007. Epub 2016 Mar 17.
Abstract
Glycosylphosphatidylinositol (GPI) is a glycolipid that anchors >150 various proteins to the cell surface. At least 27 genes are involved in biosynthesis and transport of GPI-anchored proteins (GPI-APs). To date, mutations in 13 of these genes are known to cause inherited GPI deficiencies (IGDs), and all are inherited as recessive traits. IGDs mainly manifest as intellectual disability, epilepsy, coarse facial features, and multiple organ anomalies. These symptoms are caused by the decreased surface expression of GPI-APs or by structural abnormalities of GPI. Here, we present five affected individuals (from two consanguineous families from Egypt and Pakistan and one non-consanguineous family from Japan) who show intellectual disability, hypotonia, and early-onset seizures. We identified pathogenic variants in PIGG, a gene in the GPI pathway. In the consanguineous families, homozygous variants c.928C>T (p.Gln310( *)) and c.2261+1G>C were found, whereas the Japanese individual was compound heterozygous for c.2005C>T (p.Arg669Cys) and a 2.4 Mb deletion involving PIGG. PIGG is the enzyme that modifies the second mannose with ethanolamine phosphate, which is removed soon after GPI is attached to the protein. Physiological significance of this transient modification has been unclear. Using B lymphoblasts from affected individuals of the Egyptian and Japanese families, we revealed that PIGG activity was almost completely abolished; however, the GPI-APs had normal surface levels and normal structure, indicating that the pathogenesis of PIGG deficiency is not yet fully understood. The discovery of pathogenic variants in PIGG expands the spectrum of IGDs and further enhances our understanding of this etiopathogenic class of intellectual disability.
Keywords
Abnormalities, Multiple/genetics, Adolescent, Cell Line, Tumor, Child, Consanguinity, Egypt, *Genetic Variation, Genotyping Techniques, Glycosylphosphatidylinositols/*genetics/metabolism, HEK293 Cells, Heterozygote, Homozygote, Humans, Infant, Intellectual Disability/*genetics, Japan, Mannosyltransferases/*genetics, Muscle Hypotonia/*genetics, Mutation, Pakistan, Pedigree, Seizures/*genetics, Young Adult
Pubmed
Create date
20/05/2019 13:52
Last modification date
14/12/2019 7:26
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