title: PIGN mutations cause congenital anomalies, developmental delay, hypotonia, epilepsy, and progressive cerebellar atrophy.
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.
authors.affiliation: Department of Human Genetics, Graduate School of Medicine, Yokohama City University, 3-9 Fukuura, Kanazawa-ku, Yokohama, 236-0004, Japan, t116017g@yokohama-cu.ac.jp.
authors.forename: Chihiro
authors.initials: C
authors.lastname: Ohba
authors.forename: Nobuhiko
authors.initials: N
authors.lastname: Okamoto
authors.forename: Yoshiko
authors.initials: Y
authors.lastname: Murakami
authors.forename: Yasuhiro
authors.initials: Y
authors.lastname: Suzuki
authors.forename: Yoshinori
authors.initials: Y
authors.lastname: Tsurusaki
authors.forename: Mitsuko
authors.initials: M
authors.lastname: Nakashima
authors.forename: Noriko
authors.initials: N
authors.lastname: Miyake
authors.forename: Fumiaki
authors.initials: F
authors.lastname: Tanaka
authors.forename: Taroh
authors.initials: T
authors.lastname: Kinoshita
authors.forename: Naomichi
authors.initials: N
authors.lastname: Matsumoto
authors.forename: Hirotomo
authors.initials: H
authors.lastname: Saitsu
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics*; D001921:Brain / Q000002:abnormalities; D051927:CD24 Antigen / Q000378:metabolism; D002526:Cerebellar Diseases / Q000235:genetics / Q000473:pathology; D002648:Child; D002675:Child, Preschool; D000013:Congenital Abnormalities / Q000235:genetics; D002658:Developmental Disabilities / Q000235:genetics; D004827:Epilepsy / Q000235:genetics; D005260:Female; D058851:GPI-Linked Proteins / Q000378:metabolism; D006579:Heterozygote; D006801:Humans; D008297:Male; D009123:Muscle Hypotonia / Q000235:genetics; D009154:Mutation; D010375:Pedigree; D010770:Phosphotransferases / Q000235:genetics*; D017452:Receptors, IgG / Q000378:metabolism
chemical_list: D051927:CD24 Antigen; C497889:CD24 protein, human; C428200:FCGR3B protein, human; D058851:GPI-Linked Proteins; D017452:Receptors, IgG; C561296:PIGN protein, human; D010770:Phosphotransferases