PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy
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Abstract
Defects of the human glycosylphosphatidylinositol (GPI) anchor biosynthetic pathway show a broad range of clinical phenotypes. A homozygous mutation in PIGN, a member of genes involved in the GPI anchor-synthesis pathway, was previously reported to cause dysmorphic features, multiple congenital anomalies, severe neurological impairment, and seizure in a consanguineous family. Here, we report two affected siblings with compound heterozygous PIGN mutations [c.808T >C (p.Ser270Pro) and c.963G >A] showing congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy. The c.808C >T mutation altered an evolutionarily conserved amino acid residue (Ser270), while reverse transcription-PCR and sequencing demonstrated that c.963G >A led to aberrant splicing, in which two mutant transcripts with premature stop codons (p.Ala322Valfs*24 and p.Glu308Glyfs*2) were generated. Expression of GPI-anchored proteins such as CD16 and CD24 on granulocytes from affected siblings was significantly decreased, and expression of the GPI-anchored protein CD59 in PIGN-knockout human embryonic kidney 293 cells was partially or hardly restored by transient expression of p.Ser270Pro and p.Glu308Glyfs*2 mutants, respectively, suggesting severe and complete loss of PIGN activity. Our findings confirm that developmental delay, hypotonia, and epilepsy combined with congenital anomalies are common phenotypes of PIGN mutations and add progressive cerebellar atrophy to this clinical spectrum.
Keywords
Cerebellar atrophy Compound heterozygous mutation Glycosylphosphatidylinositol anchor PIGNNotes
Acknowledgments
We would like to thank patients and their parents for their participation in this study. We also thank Nobuko Watanabe and Kana Miyanagi for technical assistance. This work was supported by the Ministry of Health, Labour, and Welfare of Japan; a Grant-in-Aid for Scientific Research (A), (B), and (C) from the Japan Society for the Promotion of Science (A: 24249019, B: 25293085 25293235, C: 23590363); the Takeda Science Foundation; the Japan Science and Technology Agency; the Strategic Research Program for Brain Sciences (11105137); and a Grant-in-Aid for Scientific Research on Innovative Areas (Transcription Cycle, Exploring molecular basis for brain diseases based on personal genomics) from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (12024421, 25129705).
Supplementary material
References
- 1.Freeze HH, Eklund EA, Ng BG, Patterson MC (2012) Neurology of inherited glycosylation disorders. Lancet Neurol 11(5):453–466. doi: 10.1016/s1474-4422(12)70040-6 PubMedCentralPubMedCrossRefGoogle Scholar
- 2.Maeda Y, Kinoshita T (2011) Structural remodeling, trafficking and functions of glycosylphosphatidylinositol-anchored proteins. Prog Lipid Res 50(4):411–424. doi: 10.1016/j.plipres.2011.05.002 PubMedCrossRefGoogle Scholar
- 3.Hansen L, Tawamie H, Murakami Y, Mang Y, ur Rehman S, Buchert R, Schaffer S, Muhammad S, Bak M, Nothen MM, Bennett EP, Maeda Y, Aigner M, Reis A, Kinoshita T, Tommerup N, Baig SM, Abou Jamra R (2013) Hypomorphic mutations in PGAP2, encoding a GPI-anchor-remodeling protein, cause autosomal-recessive intellectual disability. Am J Hum Genet 92(4):575–583. doi: 10.1016/j.ajhg.2013.03.008 Google Scholar
- 4.Krawitz PM, Murakami Y, Riess A, Hietala M, Kruger U, Zhu N, Kinoshita T, Mundlos S, Hecht J, Robinson PN, Horn D (2013) PGAP2 mutations, affecting the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation syndrome. Am J Hum Genet 92(4):584–589. doi: 10.1016/j.ajhg.2013.03.011 Google Scholar
- 5.Kvarnung M, Nilsson D, Lindstrand A, Korenke GC, Chiang SC, Blennow E, Bergmann M, Stodberg T, Makitie O, Anderlid BM, Bryceson YT, Nordenskjold M, Nordgren A (2013) A novel intellectual disability syndrome caused by GPI anchor deficiency due to homozygous mutations in PIGT. J Med Genet 50(8):521–528. doi: 10.1136/jmedgenet-2013-101654 Google Scholar
- 6.Hong Y, Maeda Y, Watanabe R, Ohishi K, Mishkind M, Riezman H, Kinoshita T (1999) Pig-n, a mammalian homologue of yeast Mcd4p, is involved in transferring phosphoethanolamine to the first mannose of the glycosylphosphatidylinositol. J Biol Chem 274(49):35099–35106Google Scholar
- 7.Maydan G, Noyman I, Har-Zahav A, Neriah ZB, Pasmanik-Chor M, Yeheskel A, Albin-Kaplanski A, Maya I, Magal N, Birk E, Simon AJ, Halevy A, Rechavi G, Shohat M, Straussberg R, Basel-Vanagaite L (2011) Multiple congenital anomalies-hypotonia-seizures syndrome is caused by a mutation in PIGN. J Med Genet 48(6):383–389. doi: 10.1136/jmg.2010.087114 Google Scholar
- 8.Saitsu H, Nishimura T, Muramatsu K, Kodera H, Kumada S, Sugai K, Kasai-Yoshida E, Sawaura N, Nishida H, Hoshino A, Ryujin F, Yoshioka S, Nishiyama K, Kondo Y, Tsurusaki Y, Nakashima M, Miyake N, Arakawa H, Kato M, Mizushima N, Matsumoto N (2013) De novo mutations in the autophagy gene WDR45 cause static encephalopathy of childhood with neurodegeneration in adulthood. Nat Genet. doi: 10.1038/ng.2562
- 9.Saitsu H, Kato M, Okada I, Orii KE, Higuchi T, Hoshino H, Kubota M, Arai H, Tagawa T, Kimura S, Sudo A, Miyama S, Takami Y, Watanabe T, Nishimura A, Nishiyama K, Miyake N, Wada T, Osaka H, Kondo N, Hayasaka K, Matsumoto N (2010) STXBP1 mutations in early infantile epileptic encephalopathy with suppression-burst pattern. Epilepsia 51(12):2397–2405. doi: 10.1111/j.1528-1167.2010.02728.x Google Scholar
- 10.Cong L, Ran FA, Cox D, Lin S, Barretto R, Habib N, Hsu PD, Wu X, Jiang W, Marraffini LA, Zhang F (2013) Multiplex genome engineering using CRISPR/Cas systems. Science 339(6121):819–823. doi: 10.1126/science.1231143 PubMedCentralPubMedCrossRefGoogle Scholar
- 11.McKean DM, Niswander L (2012) Defects in GPI biosynthesis perturb Cripto signaling during forebrain development in two new mouse models of holoprosencephaly. Biology open 1(9):874–883. doi: 10.1242/bio.20121982 PubMedCentralPubMedCrossRefGoogle Scholar
- 12.Freeze HH (2013) Understanding human glycosylation disorders: biochemistry leads the charge. J Biol Chem 288(10):6936–6945. doi: 10.1074/jbc.R112.429274 PubMedCentralPubMedCrossRefGoogle Scholar
- 13.Krawitz PM, Murakami Y, Hecht J, Kruger U, Holder SE, Mortier GR, Delle Chiaie B, De Baere E, Thompson MD, Roscioli T, Kielbasa S, Kinoshita T, Mundlos S, Robinson PN, Horn D (2012) Mutations in PIGO, a member of the GPI-anchor-synthesis pathway, cause hyperphosphatasia with mental retardation. Am J Hum Genet 91(1):146–151. doi: 10.1016/j.ajhg.2012.05.004 Google Scholar
- 14.Almeida AM, Murakami Y, Layton DM, Hillmen P, Sellick GS, Maeda Y, Richards S, Patterson S, Kotsianidis I, Mollica L, Crawford DH, Baker A, Ferguson M, Roberts I, Houlston R, Kinoshita T, Karadimitris A (2006) Hypomorphic promoter mutation in PIGM causes inherited glycosylphosphatidylinositol deficiency. Nat Med 12(7):846–851. doi: 10.1038/nm1410 Google Scholar
- 15.Johnston JJ, Gropman AL, Sapp JC, Teer JK, Martin JM, Liu CF, Yuan X, Ye Z, Cheng L, Brodsky RA, Biesecker LG (2012) The phenotype of a germline mutation in PIGA: the gene somatically mutated in paroxysmal nocturnal hemoglobinuria. Am J Hum Genet 90(2):295–300. doi: 10.1016/j.ajhg.2011.11.031 Google Scholar