BACKGROUND: This study reports on a hitherto undescribed autosomal recessive syndrome characterised by dysmorphic features and multiple congenital anomalies together with severe neurological impairment, chorea and seizures leading to early death, and the identification of a gene involved in the pathogenesis of the disease. METHODS: Homozygosity mapping was performed using Affymetrix Human Mapping 250k NspI arrays. Sequencing of all coding exons of the candidate genes was performed with primer sets designed using the Primer3 program. Fluorescence activated cell sorting was performed using conjugated antibody to CD59. Staining, acquisition and analysis were performed on a FACSCalibur flow cytometer. RESULTS: Using homozygosity mapping, the study mapped the disease locus to 18q21.32-18q22.1 and identified the disease-causing mutation, c.2126G→A (p.Arg709Gln), in PIGN, which encodes glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase 1, a protein involved in GPI-anchor biosynthesis. Arginine at the position 709 is a highly evolutionarily conserved residue located in the PigN domain. The expression of GPI linked protein CD59 on fibroblasts from patients as compared to that in a control individual showed a 10-fold reduction in expression, confirming the pathogenic consequences of the mutation on GPI dependent protein expression. CONCLUSIONS: The abundant expression of PIGN in various tissues is compatible with the diverse phenotypic features observed in the patients and with the involvement of multiple body systems. The presence of developmental delay, hypotonia, and epilepsy combined with multiple congenital anomalies, especially anorectal anomalies, should lead a clinician to suspect a GPI deficiency related disorder.
BACKGROUND: This study reports on a hitherto undescribed autosomal recessive syndrome characterised by dysmorphic features and multiple congenital anomalies together with severe neurological impairment, chorea and seizures leading to early death, and the identification of a gene involved in the pathogenesis of the disease. METHODS: Homozygosity mapping was performed using Affymetrix Human Mapping 250k NspI arrays. Sequencing of all coding exons of the candidate genes was performed with primer sets designed using the Primer3 program. Fluorescence activated cell sorting was performed using conjugated antibody to CD59. Staining, acquisition and analysis were performed on a FACSCalibur flow cytometer. RESULTS: Using homozygosity mapping, the study mapped the disease locus to 18q21.32-18q22.1 and identified the disease-causing mutation, c.2126G→A (p.Arg709Gln), in PIGN, which encodes glycosylphosphatidylinositol (GPI) ethanolamine phosphate transferase 1, a protein involved in GPI-anchor biosynthesis. Arginine at the position 709 is a highly evolutionarily conserved residue located in the PigN domain. The expression of GPI linked protein CD59 on fibroblasts from patients as compared to that in a control individual showed a 10-fold reduction in expression, confirming the pathogenic consequences of the mutation on GPI dependent protein expression. CONCLUSIONS: The abundant expression of PIGN in various tissues is compatible with the diverse phenotypic features observed in the patients and with the involvement of multiple body systems. The presence of developmental delay, hypotonia, and epilepsy combined with multiple congenital anomalies, especially anorectal anomalies, should lead a clinician to suspect a GPI deficiency related disorder.
Authors: Jennifer J Johnston; Andrea L Gropman; Julie C Sapp; Jamie K Teer; Jodie M Martin; Cyndi F Liu; Xuan Yuan; Zhaohui Ye; Linzhao Cheng; Robert A Brodsky; Leslie G Biesecker Journal: Am J Hum Genet Date: 2012-02-02 Impact factor: 11.025
Authors: D Marques-da-Silva; R Francisco; D Webster; V Dos Reis Ferreira; J Jaeken; T Pulinilkunnil Journal: J Inherit Metab Dis Date: 2017-07-19 Impact factor: 4.982
Authors: Barbara Wiśniowiecka-Kowalnik; Monika Kastory-Bronowska; Magdalena Bartnik; Katarzyna Derwińska; Wanda Dymczak-Domini; Dorota Szumbarska; Ewa Ziemka; Krzysztof Szczałuba; Maciej Sykulski; Tomasz Gambin; Anna Gambin; Chad A Shaw; Tadeusz Mazurczak; Ewa Obersztyn; Ewa Bocian; Paweł Stankiewicz Journal: Eur J Hum Genet Date: 2012-10-03 Impact factor: 4.246
Authors: Malcolm F Howard; Yoshiko Murakami; Alistair T Pagnamenta; Cornelia Daumer-Haas; Björn Fischer; Jochen Hecht; David A Keays; Samantha J L Knight; Uwe Kölsch; Ulrike Krüger; Steffen Leiz; Yusuke Maeda; Daphne Mitchell; Stefan Mundlos; John A Phillips; Peter N Robinson; Usha Kini; Jenny C Taylor; Denise Horn; Taroh Kinoshita; Peter M Krawitz Journal: Am J Hum Genet Date: 2014-01-16 Impact factor: 11.025