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Normal Function
The PIGN gene provides instructions for making an enzyme called GPI ethanolamine phosphate transferase 1. This enzyme takes part in a series of steps that produce a molecule called a glycophosphatidylinositol (GPI) anchor. A GPI anchor attaches to many different proteins inside the cell, which are known as GPI-anchored proteins. After a GPI anchor binds to a protein, the GPI anchor attaches itself to the outer surface of the cell membrane, ensuring that the GPI-anchored protein is available when it is needed. A GPI anchor is made up of many different pieces and is assembled in a cell structure called the endoplasmic reticulum, which is involved in protein processing and transport.
GPI-anchored proteins have a variety of roles, which include helping cells attach to one another (cell adhesion), relaying signals into the cells (cell signaling), and protecting cells from foreign invaders (cellular immunity).
Health Conditions Related to Genetic Changes
Fryns syndrome
Variants (also called mutations) in the PIGN gene have been found to cause Fryns syndrome in some people. This condition affects the development of many parts of the body. Most people with Fryns syndrome have a defect in the muscle that separates the abdomen from the chest cavity (the diaphragm). The most common defect is a congenital diaphragmatic hernia, which is a hole in the diaphragm that develops before birth. Additional signs and symptoms can include distinctive facial features and abnormalities of the fingers and toes.
Most of the PIGN gene variants that are associated with Fryns syndrome cause cells to produce a shortened version of the enzyme that does not function properly. These variants are known as "loss-of-function variants" because they reduce the amount of functional GPI ethanolamine phosphate transferase 1 enzyme that is available to modify the GPI anchor. As a result, the GPI anchor cannot deliver proteins to their proper places on the cell membrane. This disrupts critical developmental pathways, which leads to the signs and symptoms seen in people with Fryns syndrome.
More About This Health ConditionOther disorders
Variants in the PIGN gene can also cause a condition called multiple congenital anomalies-hypotonia-seizures syndrome 1 (MCAHS1). Many of the signs and symptoms seen in people with MCAHS1 overlap with those seen in people with Fryns syndrome. However, people with MCAHS1 typically do not have a congenital diaphragmatic hernia. Many of the PIGN gene variants that cause MCAHS1 lead to changes in single protein building blocks (amino acids) in the GPI ethanolamine phosphate transferase 1 enzyme. Though the features seen in people with MCAHS1 are typically considered to be less severe than those seen in people with Fryns syndrome, individuals with MCAHS1 usually do not survive past early childhood. People with MCAHS1 have variants in both copies of the PIGN gene.
Some people with PIGN gene variants have neurologic signs and symptoms that are similar to those seen in people with Fryns syndrome or MCAHS1 without having all of the features of these disorders. These individuals may have weak muscle tone (hypotonia), developmental delays, intellectual disabilities, movement disorders, and seizures. Researchers are working to learn more about the range of features that can be associated with changes in the PIGN gene.
Other Names for This Gene
- MCD4
- Phosphatidylinositol glycan anchor biosynthesis class N protein
- PIG-N
Additional Information & Resources
Tests Listed in the Genetic Testing Registry
Scientific Articles on PubMed
Catalog of Genes and Diseases from OMIM
References
- Alessandri JL, Gordon CT, Jacquemont ML, Gruchy N, Ajeawung NF, Benoist G, Oufadem M, Chebil A, Duffourd Y, Dumont C, Gerard M, Kuentz P, Jouan T, Filippini F, Nguyen TTM, Alibeu O, Bole-Feysot C, Nitschke P, Omarjee A, Ramful D, Randrianaivo H, Doray B, Faivre L, Amiel J, Campeau PM, Thevenon J. Recessive loss of function PIGN alleles, including an intragenic deletion with founder effect in La Reunion Island, in patients with Fryns syndrome. Eur J Hum Genet. 2018 Mar;26(3):340-349. doi: 10.1038/s41431-017-0087-x. Epub 2018 Jan 12. Citation on PubMed
- Loong L, Tardivo A, Knaus A, Hashim M, Pagnamenta AT, Alt K, Bohrer-Rabel H, Caro-Llopis A, Cole T, Distelmaier F, Edery P, Ferreira CR, Jezela-Stanek A, Kerr B, Kluger G, Krawitz PM, Kuhn M, Lemke JR, Lesca G, Lynch SA, Martinez F, Maxton C, Mierzewska H, Monfort S, Nicolai J, Orellana C, Pal DK, Ploski R, Quarrell OW, Rosello M, Rydzanicz M, Sabir A, Smigiel R, Stegmann APA, Stewart H, Stumpel C, Szczepanik E, Tzschach A, Wolfe L, Taylor JC, Murakami Y, Kinoshita T, Bayat A, Kini U. Biallelic variants in PIGN cause Fryns syndrome, multiple congenital anomalies-hypotonia-seizures syndrome, and neurologic phenotypes: A genotype-phenotype correlation study. Genet Med. 2023 Jan;25(1):37-48. doi: 10.1016/j.gim.2022.09.007. Epub 2022 Nov 2. Citation on PubMed
- Slavotinek A. Fryns Syndrome. 2007 Apr 18 [updated 2020 Sep 17]. In: Adam MP, Feldman J, Mirzaa GM, Pagon RA, Wallace SE, Amemiya A, editors. GeneReviews(R) [Internet]. Seattle (WA): University of Washington, Seattle; 1993-2025. Available from http://www.ncbi.nlm.nih.gov/books/NBK1459/ Citation on PubMed
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