HGNC Approved Gene Symbol: PIGN
Cytogenetic location: 18q21.33 Genomic coordinates (GRCh38) : 18:62,017,615-62,187,056 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 18q21.33 | Multiple congenital anomalies-hypotonia-seizures syndrome 1 | 614080 | Autosomal recessive | 3 |
The PIGN gene encodes glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase-1, also called phosphatidylinositol-glycan biosynthesis class N protein, which is involved in GPI-anchor biosynthesis. GPI-anchored proteins comprise a well-characterized family of proteins that must acquire a GPI anchor and traffic from their site of synthesis, i.e., the endoplasmic reticulum (ER), to their final destination, the cell surface (summary by Maydan et al., 2011). The common backbone of GPIs is assembled by the sequential additions of sugar and phosphoethanolamine (EtNP) components to phosphatidylinositol (summary by Gaynor et al., 1999).
For information on the PIG gene family and the roles of PIG proteins in GPI biosynthesis, see PIGA (311770).
In a screen to isolate yeast mutants defective for bud emergence and polarized growth, Gaynor et al. (1999) identified yeast Mcd4. By database searching, they identified cDNA clones encoding human PIGN, which they called MCD4. PIGN encodes a deduced 931-amino acid protein with 14 predicted transmembrane domains, potential N-linked glycosylation sites, an ER retrieval motif, and a stop-transfer sequence predicted to direct translocation into the ER. PIGN has a hydrophilic N-terminal ER luminal domain that contains motifs conserved in mammalian phosphodiesterases and pyrophosphatases. PIGN shares sequence identity with its counterparts in S. cerevisiae (35%), S. pombe (34%), and mouse (87%).
Using subcellular fractionation and sucrose density gradient experiments, Gaynor et al. (1999) demonstrated that yeast Mcd4 is localized in the ER. Using tunicamycin and endo H treatment, they showed that the 6 N-terminal N-linked glycosylation sites of Mcd4 are utilized. They hypothesized that MCD4 is retained in the ER and is unlikely to cycle through the Golgi. Yeast Mcd4 mutants exhibited marked morphologic defects as well as an ER-to-Golgi transport defect specific for GPI-anchored proteins. Gaynor et al. (1999) concluded that MCD4 is a component of the eukaryotic GPI anchor synthesis pathway.
Hong et al. (1999) cloned mouse Pign and disrupted the protein in F9 embryonal carcinoma cells. The first mannose (Man1) in the GPI precursors was not modified by phosphoethanolamine in the knockout cells, but these cells were still capable of generating further modified GPI species. Hong et al. (1999) concluded that Pign is involved in the addition of EtNP to Man1 but that its modification is not essential for the surface expression of GPI-anchored proteins.
Burrell et al. (2013) found evidence for impaired replication fork progression and increased DNA replication stress in cancer chromosomal instability (CIN)+ colorectal cancer cells relative to CIN- colorectal cancer cells, with structural chromosome abnormalities precipitating chromosome missegregation in mitosis. Burrell et al. (2013) identified 3 CIN suppressor genes (PIGN; MEX3C, 606097; and ZNF516, 615114) encoded on chromosome 18q that are subject to frequent copy number loss in CIN+ colorectal cancer cells. Chromosome 18q loss was temporally associated with aneuploidy onset at the adenoma-carcinoma transition. CIN suppressor gene silencing led to DNA replication stress, structural chromosome abnormalities, and chromosome missegregation. Supplementing cells with nucleosides, to alleviate replication-associated damage, reduced the frequency of chromosome segregation errors after CIN suppressor gene silencing, and attenuated segregation errors and DNA damage in CIN+ cells. Burrell et al. (2013) concluded that their data implicated a central role for replication stress in the generation of structural and numerical CIN.
Maydan et al. (2011) determined that the PIGN gene contains 31 exons spanning 142.8 kb. There are 29 coding exons.
Maydan et al. (2011) stated that the PIGN gene maps to chromosome 18q21.33.
By homozygosity mapping followed by candidate gene sequencing in affected members of a consanguineous Arab Israeli family with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), Maydan et al. (2011) identified a homozygous mutation in the PIGN gene (R709Q; 606097.0001). Fibroblasts from 2 patients showed a 10-fold reduction in expression of the GPI-linked protein CD59 (107271), confirming a pathogenic influence of the mutation on GPI function. The phenotype was characterized by lack of psychomotor development, seizures, dysmorphic features, and variable congenital anomalies involving the cardiac, urinary, and gastrointestinal systems. The abundant expression of PIGN in various tissues was compatible with diverse phenotypic features and with involvement of multiple body systems in the patients.
In 2 Japanese sibs with severely delayed psychomotor development, hypotonia, nystagmus, seizures, and dysmorphic features, Ohba et al. (2014) identified compound heterozygous mutations in the PIGN gene (606097.0002 and 606097.0003). The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family. Patient granulocytes showed 26 to 54% levels of GPI-anchored proteins CD16 (see 146740) and CD24 (600074). Transient expression of the mutations in PIGN-null HEK293 cells showed decreased expression of CD59, consistent with severe or complete loss of PIGN activity.
In a 6-year-old girl, born of consanguineous Israeli Arab parents, with MCAHS1, Khayat et al. (2016) identified a homozygous missense mutation in the PIGN gene (D252V; 606097.0004). The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. Patient granulocytes showed significantly decreased expression of the GPI-anchored protein CD24 (600074) compared to controls, suggesting that the mutation was deleterious to PIGN function.
In 2 sisters with MCAHS1, Fleming et al. (2016) identified compound heterozygosity for a truncating and splice site mutation in the PIGN gene (606097.0005 and 606097.0006). An unrelated patient with a less severe phenotype was compound heterozygous for 2 missense variants in the PIGN gene. In addition, a severely affected infant was compound heterozygous for a frameshift mutation (606097.0007) and an intragenic deletion (606097.0008), predicted to result in a complete loss of PIGN. The findings suggested a genotype/phenotype correlation with truncating or loss of function mutations resulting in a more severe phenotype compared to missense mutations.
By homozygosity mapping followed by candidate gene sequencing in affected members of a consanguineous Arab Israeli family with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), Maydan et al. (2011) identified a homozygous 2126G-A transition in exon 23 of the PIGN gene, resulting in an arg709-to-gln (R709Q) substitution in a highly conserved residue in the PigN domain. The mutation was not found in 438 Arab controls, but was identified in heterozygosity in 1 individual from the same geographic region, representing carrier status. Fibroblasts from 2 patients showed a 10-fold reduction in expression of the GPI-linked protein CD59, confirming a pathogenic influence of the mutation on GPI function.
In 2 Japanese sibs with MCAHS1 (614080), Ohba et al. (2014) identified compound heterozygous mutations in the PIGN gene. One was a c.808T-C transition, resulting in a ser270-to-pro (S270P) substitution at a highly conserved residue, and the other was a c.963G-A transition at the last base of exon 10, resulting in abnormal splicing. RT-PCR analysis showed that the c.963G-A transition led to 2 aberrant transcripts causing premature termination: Ala322ValfsTer24 and Glu308GlyfsTer2. The 2 aberrant transcripts were degraded by nonsense-mediated mRNA decay. The mutations, which were found by whole-exome sequencing, segregated with the disorder in the family and were present in less than 1% of the dbSNP (build 135) database and absent in the Exome Variant Server database. S270P was absent from 406 in-house control exomes, but c.963G-A was found in the heterozygous state in 1 control. Patient granulocytes showed 26 to 54% levels of GPI-anchored proteins CD16 and CD24. Transient expression of the mutations in PIGN-null HEK293 cells showed decreased expression of CD59, consistent with severe or complete loss of PIGN activity.
In a 6-year-old Japanese boy with MCAHS1, Nakagawa et al. (2016) identified a heterozygous S270P substitution in the PIGN gene, inherited from the unaffected father, and an intragenic microdeletion encompassing exons 2 to 14 of the PIGN gene, inherited from the unaffected mother. The missense mutation, which was found by targeted exome sequencing, was not found in 451 in-house Japanese control exomes. The deletion was found by PCR analysis. This information was used for prenatal genetic testing of amniotic fluid in a subsequent pregnancy: the fetus carried only the S270P mutation in the heterozygous state.
For discussion of the c.963G-A transition in the PIGN gene that was found in compound heterozygous state in 2 patients with MCAHS1 (614080) by Ohba et al. (2014), see 606097.0002.
In a 6-year-old girl, born of consanguineous Israeli Arab parents, with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), Khayat et al. (2016) identified a homozygous c.755A-T transversion (chr18.59,814,254A-T) in exon 9 of the PIGN gene, resulting in an asp252-to-val (D252V) substitution. The mutation, which was found by exome sequencing and confirmed by Sanger sequencing, was filtered against the 1000 Genomes Project and Exome Sequencing Project databases, and found to segregate with the disorder in the family. Patient granulocytes showed significantly decreased expression of the GPI-anchored protein CD24 (600074) compared to controls, suggesting that the mutation was deleterious to PIGN function.
In 2 sisters (patients 1 and 2), born of unrelated Caucasian parents, with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), Fleming et al. (2016) identified compound heterozygous mutations in the PIGN gene: a c.2340T-A transversion (c.2340T-A, NM_176787) in exon 25, resulting in a tyr780-to-ter (Y780X) substitution in the PIGN domain inherited from the unaffected mother, and a c.1434+5G-A transition (606097.0006) in intron 17 inherited from the unaffected father. The mutations were found by whole-exome sequencing. The Y780X mutation was not found in the Exome Sequencing Project (ESP) database, but was found in 1 of 13,412 alleles in the ExAC database. The paternally inherited splice site mutation was found in 1 of 3,039 African American alleles in the ESP, but not in 6,595 European American alleles in the ESP. In the ExAC database, the splice site mutation was found in 1 of 5,512 African alleles and 1 in 28,268 European alleles. Functional studies of the variants and studies of patient cells were not performed. The sisters also carried a paternally inherited mutation in the SCN1B gene (600235), which is associated with GEFS+ (604233), and a maternally inherited mutation in the CPA6 gene (609562), which is associated with febrile seizures (614418). There was no family history of seizures.
For discussion of the c.1434+5G-A transition (c.1434+5G-A, NM_176787) in intron 17 of the PIGN gene, predicted to result in a splice site mutation, that was found in compound heterozygous state in 2 sisters with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080) by Fleming et al. (2016), see 606097.0005.
In an infant (patient 4) with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), Fleming et al. (2016) identified compound heterozygous mutations in the PIGN gene: a maternally inherited c.548_549+6del (c.548_549+6del, NM_176787), resulting in a frameshift (Leu183fs), and a paternally inherited intragenic deletion of part of exon 5 as well as exons 6 and 7 (606097.0008). The maternal mutation, which was found by whole-exome sequencing, was not found in the Exome Sequencing Project or ExAC databases.
For discussion of the intragenic deletion of part of exon 5 as well as exons 6 and 7 (chr18.59,821,582_59,824,939del, GRCh37) of the PIGN gene that was found in compound heterozygous state in a patient with multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080) by Fleming et al. (2016), see 606097.0007.
In 2 sibs (NSGC7.3 and NSGC7.4), who were fetuses, with a severe form of multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), but with a clinical diagnosis of Fryns syndrome (FRNS; 229850), McInerney-Leo et al. (2016) identified compound heterozygous mutations in the PIGN gene: a c.1966C-T transition (c.1966C-T, NM_176787.4) in exon 21, resulting in a glu656-to-ter (E656X) substitution in a highly conserved region, and a G-to-C transversion in intron 18 (c.1674+1G-C), resulting in aberrant splicing and premature termination. The mutations, which were found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. They were filtered against the dbSNP, 1000 Genomes Project, and ExAC databases.
For discussion of the G-to-C transversion in intron 18 (c.1674+1G-C, NM_176787.4) of the PIGN gene, resulting in aberrant splicing, that was found in compound heterozygous state in 2 fetuses with a severe form of multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080) by McInerney-Leo et al. (2016), see 606097.0009.
In a fetus (COLL-2.3) with a severe form of multiple congenital anomalies-hypotonia-seizures syndrome (MCAHS1; 614080), but with a clinical diagnosis of Fryns syndrome (FRNS; 229850), McInerney-Leo et al. (2016) identified a homozygous c.694A-T transversion (c.694A-T, NM_176787.4) in exon 9 of the PIGN gene, resulting in a lys232-to-ter (K232X) substitution. The mutation, which was found by whole-exome sequencing and confirmed by Sanger sequencing, segregated with the disorder in the family. It was filtered against the dbSNP, 1000 Genomes Project, and ExAC databases.
Burrell, R. A., McClelland, S. E., Endesfelder, D., Groth, P., Weller, M.-C., Shaikh, N., Domingo, E., Kanu, N., Dewhurst, S. M., Gronroos, E., Chew, S. K., Rowan, A. J., and 9 others. Replication stress links structural and numerical cancer chromosomal instability. Nature 494: 492-496, 2013. Note: Erratum: Nature 500: 490 only, 2013. [PubMed: 23446422] [Full Text: https://doi.org/10.1038/nature11935]
Fleming, L., Lemmon, M., Beck, N., Johnson, M., Mu, W., Murdock, D., Bodurtha, J., Hoover-Fong, J., Cohn, R., Bosemani, T., Baranano, K., Hamosh, A. Genotype-phenotype correlation of congenital anomalies in multiple congenital anomalies hypotonia seizures syndrome (MCAHS1)/PIGN-related epilepsy. Am. J. Med. Genet. 170A: 77-86, 2016. [PubMed: 26394714] [Full Text: https://doi.org/10.1002/ajmg.a.37369]
Gaynor, E. C., Mondesert, G., Grimme, S. J., Reed, S. I., Orlean, P., Emr, S. D. MCD4 encodes a conserved endoplasmic reticulum membrane protein essential for glycosylphosphatidylinositol anchor synthesis in yeast. Molec. Biol. Cell 10: 627-648, 1999. [PubMed: 10069808] [Full Text: https://doi.org/10.1091/mbc.10.3.627]
Hong, Y., Maeda, Y., Watanabe, R., Ohishi, K., Mishkind, M., Riezman, H., Kinoshita, T. Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol. J. Biol. Chem. 274: 35099-35106, 1999. [PubMed: 10574991] [Full Text: https://doi.org/10.1074/jbc.274.49.35099]
Khayat, M., Tilghman, J. M., Chervinsky, I., Zalman, L., Chakravarti, A., Shalev, S. A. A PIGN mutation responsible for multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1) in an Israeli-Arab family. Am. J. Med. Genet. 170A: 176-182, 2016. [PubMed: 26364997] [Full Text: https://doi.org/10.1002/ajmg.a.37375]
Maydan, G., Noyman, I., Har-Zahav, A., Neriah, Z. B., Pasmanik-Chor, M., Yeheskel, A., Albin-Kaplanski, A., Maya, I., Magal, N., Birk, E., Simon, A. J., Halevy, A., Rechavi, G., Shohat, M., Straussberg, R., Basel-Vanagaite, L. Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN. J. Med. Genet. 48: 383-389, 2011. [PubMed: 21493957] [Full Text: https://doi.org/10.1136/jmg.2010.087114]
McInerney-Leo, A. M., Harris, J. E., Gattas, M., Peach, E. E., Sinnott, S., Dudding-Byth, T., Rajagopalan, S., Barnett, C. P., Anderson, L. K., Wheeler, L., Brown, M. A., Leo, P. J., Wicking, C., Duncan, E. L. Fryns syndrome associated with recessive mutations in PIGN in two separate families. Hum. Mutat. 37: 695-702, 2016. [PubMed: 27038415] [Full Text: https://doi.org/10.1002/humu.22994]
Nakagawa, T., Taniguchi-Ikeda, M., Murakami, Y., Nakamura, S., Motooka, D., Emoto, T., Satake, W., Nishiyama, M., Toyoshima, D., Morisada, N., Takada, S., Tairaku, S., Okamoto, N., Morioka, I., Kurahashi, H., Toda, T., Kinoshita, T., Iijima, K. A novel PIGN mutation and prenatal diagnosis of inherited glycosylphosphatidylinositol deficiency. Am. J. Med. Genet. 170A: 183-188, 2016. [PubMed: 26419326] [Full Text: https://doi.org/10.1002/ajmg.a.37397]
Ohba, C., Okamoto, N., Murakami, Y., Suzuki, Y., Tsurusaki, Y., Nakashima, M., Miyake, N., Tanaka, F., Kinoshita, T., Matsumoto, N., Saitsu, H. PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy. Neurogenetics 15: 85-92, 2014. Note: Erratum: Neurogenetics 15: 93 only, 2014. [PubMed: 24253414] [Full Text: https://doi.org/10.1007/s10048-013-0384-7]