A novel mutation deep within intron 7 of the GBA gene causes Gaucher disease

被引:11
|
作者
Malekkou, Anna [1 ,2 ]
Sevastou, Ioanna [1 ,6 ,7 ]
Mavrikiou, Gavriella [1 ]
Georgiou, Theodoros [1 ,2 ]
Vilageliu, Lluisa [3 ]
Moraitou, Marina [4 ]
Michelakakis, Helen [4 ]
Prokopiou, Chrystalla [5 ]
Drousiotou, Anthi [1 ,2 ]
机构
[1] Cyprus Inst Neurol & Genet, Dept Biochem Genet, Nicosia, Cyprus
[2] Cyprus Sch Mol Med, Nicosia, Cyprus
[3] Univ Barcelona, Dept Genet, IBUB, CIBERER,Fac Biol, Barcelona, Spain
[4] Inst Child Hlth, Dept Enzymol & Cellular Funct, Athens, Greece
[5] Limassol Gen Hosp, Dept Haematol, Limassol, Cyprus
[6] UCL Queen Sq Inst Neurol, Reta Lila Weston Inst, London, England
[7] UCL Queen Sq Inst Neurol, Dept Clin & Movement Neurosci, London, England
来源
MOLECULAR GENETICS & GENOMIC MEDICINE | 2020年 / 8卷 / 03期
关键词
Cypriot; deep intronic mutation; Gaucher disease; GBA; glucocerebrosidase; HUMAN GLUCOCEREBROSIDASE GENE; IDENTIFICATION; DEFICIENCY; SEQUENCE;
D O I
10.1002/mgg3.1090
中图分类号
Q3 [遗传学];
学科分类号
071007 ; 090102 ;
摘要
Background Mutations in the GBA gene that encodes the lysosomal enzyme acid beta-glucocerebrosidase cause Gaucher disease (GD), the most common lysosomal storage disorder. Most of the mutations are missense/nonsense, however, a few splicing mutations within or close to conserved consensus donor or acceptor splice sites have also been described. The aim of the study was to identify the mutation(s) in a Cypriot patient with type I GD. Methods The genomic DNA of the proband was screened for nine common mutations using Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) analysis. All exons and exon-intron boundaries, and the 5'UTR and 3'UTR regions of the GBA gene, were investigated by Sanger sequencing. RNA analysis was performed using standard procedures, and the abnormal transcript was further cloned into pGEM-T-Easy plasmid vector and sequenced. The relevant intronic region was further sequenced by the Sanger method to identify the genetic variant. Results A novel point mutation, g.12599C > A (c.999 + 242C > A), was detected deep in intron 7 of the GBA gene. This type of mutation has been previously described for other diseases but this is the first time, as far as we know, that it is described for GD. This mutation creates a new donor splice site leading to aberrant splicing and resulting in the insertion of the first 239nt of intron 7 as a pseudoexon in the mRNA, creating a premature stop codon. Conclusion This study expands the mutation spectrum of GD and highlights the importance of RNA sequencing for the molecular diagnosis of patients bearing mutations in nonexonic regions.
引用
收藏
页数:6
相关论文
共 50 条
  • [31] Correlation between bone manifestations and variants of the GBA gene in Gaucher disease: A systematic review
    Arturo Terranova, Daniela
    Moreno Giraldo, Lina Johanna
    Satizabal-Soto, Jose Maria
    MOLECULAR GENETICS AND METABOLISM, 2023, 138 (02) : 9 - 9
  • [32] A novel deletion mutation within the carboxyl terminus of the copper-transporting ATPase gene causes Wilson disease
    Majumdar, R
    Al Jumah, M
    Al Rajeh, S
    Fraser, M
    Al Zaben, A
    Awada, A
    Al Traif, I
    Paterson, M
    JOURNAL OF THE NEUROLOGICAL SCIENCES, 2000, 179 (1-2) : 140 - 143
  • [33] Perinatal lethal Gaucher disease due to compound heterozygosity of the splicing mutations in GBA gene
    Lu, Tsai-Jung
    Hsiao, Tzu-Hung
    Wang, Jiaan-Der
    Lo, Feng-Chu
    Jhan, Pei -Pei
    Chen, Wei-Chih
    TAIWANESE JOURNAL OF OBSTETRICS & GYNECOLOGY, 2023, 62 (01): : 175 - 178
  • [34] Development of an AAV-GBA Gene Therapy for the Treatment of Type 1 Gaucher Disease
    Cheng, Ting-Wen
    Souza, David
    Tabet, Ricardos
    Wright, Katherine
    Brodfuehrer, Joanne
    Keyes, Lisa
    Rao-Dayton, Sheila
    Lewis, Patricia
    Sievers, Annette
    McCarty, Douglas M.
    Somanathan, Suryanarayan
    Pan, Clark
    Bell, Robert D.
    MOLECULAR THERAPY, 2021, 29 (04) : 251 - 251
  • [35] A novel Parkinson's disease risk variant, p. W378R, in the Gaucher's disease GBA gene
    Lubomski, Michal
    Hayes, Michael
    Kennerson, Marina
    Ellis, Melina
    Chu, Shannon
    Blackie, Jeffrey
    O'Sullivan, John D.
    Nicholson, Garth
    MOVEMENT DISORDERS, 2018, 33 (10) : 1662 - 1664
  • [36] Gaucher Disease Patient With Myoclonus Epilepsy and a Novel Mutation
    Tajima, Asako
    Ohashi, Toya
    Hamano, Shin-ichiro
    Higurashi, Norimichi
    Ida, Hiroyuki
    PEDIATRIC NEUROLOGY, 2010, 42 (01) : 65 - 68
  • [37] A Novel GBA2 Gene Missense Mutation in Spastic Ataxia
    Votsi, Christina
    Zamba-Papanicolaou, Eleni
    Middleton, Lefkos T.
    Pantzaris, Marios
    Christodoulou, Kyproula
    ANNALS OF HUMAN GENETICS, 2014, 78 (01) : 13 - 22
  • [38] The molecular mechanism of Gaucher disease caused by compound heterozygous mutations in GBA1 gene
    Liu, Qi
    Shen, Zongrui
    Pan, Hong
    Ma, Shunfei
    Xiong, Fu
    He, Fei
    FRONTIERS IN PEDIATRICS, 2023, 11
  • [39] Mutation spectrum of glucocerebrosidase gene in Pakistani patients with Gaucher disease
    Cheema, Huma A.
    Anjum, Muhammad N.
    Saeed, Anjum
    Zahoor, Muhammad Yasir
    Waheed, Nadia
    MOLECULAR GENETICS AND METABOLISM, 2020, 129 (02) : S39 - S39
  • [40] Spectrum of GBA Mutations in Patients with Gaucher Disease from Slovakia: Identification of Five Novel Mutations
    Mattosova, Slavomira
    Chandoga, Jan
    Hlavata, Anna
    Saligova, Jana
    Macekova, Danka
    ISRAEL MEDICAL ASSOCIATION JOURNAL, 2015, 17 (03): : 166 - 170