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Deleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity

Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families... Full description

Journal Title: AMERICAN JOURNAL OF HUMAN GENETICS 2012-06-08, Vol.90 (6), p.986-1001
Main Author: Lopez-Herrera, Gabriela
Other Authors: Tampella, Giacomo , Pan-Hammarström, Qiang , Herholz, Peer , Trujillo-Vargas, Claudia M , Phadwal, Kanchan , Simon, Anna Katharina , Moutschen, Michel , Etzioni, Amos , Mory, Adi , Srugo, Izhak , Melamed, Doron , Hultenby, Kjell , Liu, Chonghai , Baronio, Manuela , Vitali, Massimiliano , Philippet, Pierre , Dideberg, Vinciane , Aghamohammadi, Asghar , Rezaei, Nima , Enright, Victoria , Du, Likun , Salzer, Ulrich , Eibel, Hermann , Pfeifer, Dietmar , Veelken, Hendrik , Stauss, Hans , Lougaris, Vassilios , Plebani, Alessandro , Gertz, E. Michael , Schäffer, Alejandro A , Hammarström, Lennart , Grimbacher, Bodo
Format: Electronic Article Electronic Article
Language: English
Subjects:
Quelle: Alma/SFX Local Collection
Publisher: Cambridge, MA: Elsevier Inc
ID: ISSN: 0002-9297
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title: Deleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity
format: Article
creator:
  • Lopez-Herrera, Gabriela
  • Tampella, Giacomo
  • Pan-Hammarström, Qiang
  • Herholz, Peer
  • Trujillo-Vargas, Claudia M
  • Phadwal, Kanchan
  • Simon, Anna Katharina
  • Moutschen, Michel
  • Etzioni, Amos
  • Mory, Adi
  • Srugo, Izhak
  • Melamed, Doron
  • Hultenby, Kjell
  • Liu, Chonghai
  • Baronio, Manuela
  • Vitali, Massimiliano
  • Philippet, Pierre
  • Dideberg, Vinciane
  • Aghamohammadi, Asghar
  • Rezaei, Nima
  • Enright, Victoria
  • Du, Likun
  • Salzer, Ulrich
  • Eibel, Hermann
  • Pfeifer, Dietmar
  • Veelken, Hendrik
  • Stauss, Hans
  • Lougaris, Vassilios
  • Plebani, Alessandro
  • Gertz, E. Michael
  • Schäffer, Alejandro A
  • Hammarström, Lennart
  • Grimbacher, Bodo
subjects:
  • Adaptor Proteins
  • Adaptor Proteins, Signal Transducing - genetics
  • Agammaglobulinemia
  • Agammaglobulinemia - genetics
  • Analysis
  • Apoptosis
  • Article
  • Autoimmune diseases
  • Autoimmunity
  • Autoimmunity - genetics
  • Autophagy
  • B-Lymphocytes - cytology
  • Biological and medical sciences
  • Causes of
  • Cell activation
  • Cell Proliferation
  • Child
  • Child, Preschool
  • Childrens health
  • chromosome 4
  • Chromosome Mapping
  • Development
  • Electron
  • Female
  • Fundamental and applied biological sciences. Psychology
  • Gene mutations
  • General & internal medicine
  • Genetic
  • Genetic aspects
  • Genetic disorders
  • Genetic Linkage
  • Genetic research
  • Genetic susceptibility
  • Genetics
  • Genetics & genetic processes
  • Genetics of eukaryotes. Biological and molecular evolution
  • Genetics(clinical)
  • Genotype
  • Genotype & phenotype
  • Genotypes
  • Génétique & processus génétiques
  • Heredity
  • Homozygote
  • Human health sciences
  • Humans
  • Hypogammaglobulinemia
  • Immune system
  • Immunodeficiencies
  • Immunodeficiencies. Immunoglobulinopathies
  • Immunodeficiency
  • Immunoglobulins
  • Immunologic Deficiency Syndromes
  • Immunologic Deficiency Syndromes - genetics
  • Immunopathology
  • Immunophenotyping
  • Life sciences
  • Linkage analysis
  • Lipopolysaccharides
  • Lymphocytes
  • Lymphocytes B
  • Male
  • Medical genetics
  • Medical sciences
  • Medicin och hälsovetenskap
  • Microscopy
  • Microscopy, Electron, Transmission - methods
  • Mitogens
  • Models
  • Models, Genetic
  • Molecular and cellular biology
  • Mutation
  • Médecine générale & interne
  • Pedigree
  • Phagocytosis
  • Phenotype
  • Preschool
  • Sciences de la santé humaine
  • Sciences du vivant
  • Signal Transducing
  • Transmission
ispartof: AMERICAN JOURNAL OF HUMAN GENETICS, 2012-06-08, Vol.90 (6), p.986-1001
description: Most autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.
language: eng
source: Alma/SFX Local Collection
identifier: ISSN: 0002-9297
fulltext: fulltext
issn:
  • 0002-9297
  • 1537-6605
  • 1537-6605
url: Link


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titleDeleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity
sourceAlma/SFX Local Collection
creatorLopez-Herrera, Gabriela ; Tampella, Giacomo ; Pan-Hammarström, Qiang ; Herholz, Peer ; Trujillo-Vargas, Claudia M ; Phadwal, Kanchan ; Simon, Anna Katharina ; Moutschen, Michel ; Etzioni, Amos ; Mory, Adi ; Srugo, Izhak ; Melamed, Doron ; Hultenby, Kjell ; Liu, Chonghai ; Baronio, Manuela ; Vitali, Massimiliano ; Philippet, Pierre ; Dideberg, Vinciane ; Aghamohammadi, Asghar ; Rezaei, Nima ; Enright, Victoria ; Du, Likun ; Salzer, Ulrich ; Eibel, Hermann ; Pfeifer, Dietmar ; Veelken, Hendrik ; Stauss, Hans ; Lougaris, Vassilios ; Plebani, Alessandro ; Gertz, E. Michael ; Schäffer, Alejandro A ; Hammarström, Lennart ; Grimbacher, Bodo
creatorcontribLopez-Herrera, Gabriela ; Tampella, Giacomo ; Pan-Hammarström, Qiang ; Herholz, Peer ; Trujillo-Vargas, Claudia M ; Phadwal, Kanchan ; Simon, Anna Katharina ; Moutschen, Michel ; Etzioni, Amos ; Mory, Adi ; Srugo, Izhak ; Melamed, Doron ; Hultenby, Kjell ; Liu, Chonghai ; Baronio, Manuela ; Vitali, Massimiliano ; Philippet, Pierre ; Dideberg, Vinciane ; Aghamohammadi, Asghar ; Rezaei, Nima ; Enright, Victoria ; Du, Likun ; Salzer, Ulrich ; Eibel, Hermann ; Pfeifer, Dietmar ; Veelken, Hendrik ; Stauss, Hans ; Lougaris, Vassilios ; Plebani, Alessandro ; Gertz, E. Michael ; Schäffer, Alejandro A ; Hammarström, Lennart ; Grimbacher, Bodo
descriptionMost autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.
identifier
0ISSN: 0002-9297
1ISSN: 1537-6605
2EISSN: 1537-6605
3DOI: 10.1016/j.ajhg.2012.04.015
4PMID: 22608502
5CODEN: AJHGAG
languageeng
publisherCambridge, MA: Elsevier Inc
subjectAdaptor Proteins ; Adaptor Proteins, Signal Transducing - genetics ; Agammaglobulinemia ; Agammaglobulinemia - genetics ; Analysis ; Apoptosis ; Article ; Autoimmune diseases ; Autoimmunity ; Autoimmunity - genetics ; Autophagy ; B-Lymphocytes - cytology ; Biological and medical sciences ; Causes of ; Cell activation ; Cell Proliferation ; Child ; Child, Preschool ; Childrens health ; chromosome 4 ; Chromosome Mapping ; Development ; Electron ; Female ; Fundamental and applied biological sciences. Psychology ; Gene mutations ; General & internal medicine ; Genetic ; Genetic aspects ; Genetic disorders ; Genetic Linkage ; Genetic research ; Genetic susceptibility ; Genetics ; Genetics & genetic processes ; Genetics of eukaryotes. Biological and molecular evolution ; Genetics(clinical) ; Genotype ; Genotype & phenotype ; Genotypes ; Génétique & processus génétiques ; Heredity ; Homozygote ; Human health sciences ; Humans ; Hypogammaglobulinemia ; Immune system ; Immunodeficiencies ; Immunodeficiencies. Immunoglobulinopathies ; Immunodeficiency ; Immunoglobulins ; Immunologic Deficiency Syndromes ; Immunologic Deficiency Syndromes - genetics ; Immunopathology ; Immunophenotyping ; Life sciences ; Linkage analysis ; Lipopolysaccharides ; Lymphocytes ; Lymphocytes B ; Male ; Medical genetics ; Medical sciences ; Medicin och hälsovetenskap ; Microscopy ; Microscopy, Electron, Transmission - methods ; Mitogens ; Models ; Models, Genetic ; Molecular and cellular biology ; Mutation ; Médecine générale & interne ; Pedigree ; Phagocytosis ; Phenotype ; Preschool ; Sciences de la santé humaine ; Sciences du vivant ; Signal Transducing ; Transmission
ispartofAMERICAN JOURNAL OF HUMAN GENETICS, 2012-06-08, Vol.90 (6), p.986-1001
rights
02012 The American Society of Human Genetics
12015 INIST-CNRS
2Copyright © 2012 The American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.
3COPYRIGHT 2012 Elsevier B.V.
4Copyright Cell Press Jun 8, 2012
52012 The American Society of Human Genetics. Published by Elsevier Ltd. All right reserved. 2012 The American Society of Human Genetics
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0Lopez-Herrera, Gabriela
1Tampella, Giacomo
2Pan-Hammarström, Qiang
3Herholz, Peer
4Trujillo-Vargas, Claudia M
5Phadwal, Kanchan
6Simon, Anna Katharina
7Moutschen, Michel
8Etzioni, Amos
9Mory, Adi
10Srugo, Izhak
11Melamed, Doron
12Hultenby, Kjell
13Liu, Chonghai
14Baronio, Manuela
15Vitali, Massimiliano
16Philippet, Pierre
17Dideberg, Vinciane
18Aghamohammadi, Asghar
19Rezaei, Nima
20Enright, Victoria
21Du, Likun
22Salzer, Ulrich
23Eibel, Hermann
24Pfeifer, Dietmar
25Veelken, Hendrik
26Stauss, Hans
27Lougaris, Vassilios
28Plebani, Alessandro
29Gertz, E. Michael
30Schäffer, Alejandro A
31Hammarström, Lennart
32Grimbacher, Bodo
title
0Deleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity
1AMERICAN JOURNAL OF HUMAN GENETICS
addtitleAm J Hum Genet
descriptionMost autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.
subject
0Adaptor Proteins
1Adaptor Proteins, Signal Transducing - genetics
2Agammaglobulinemia
3Agammaglobulinemia - genetics
4Analysis
5Apoptosis
6Article
7Autoimmune diseases
8Autoimmunity
9Autoimmunity - genetics
10Autophagy
11B-Lymphocytes - cytology
12Biological and medical sciences
13Causes of
14Cell activation
15Cell Proliferation
16Child
17Child, Preschool
18Childrens health
19chromosome 4
20Chromosome Mapping
21Development
22Electron
23Female
24Fundamental and applied biological sciences. Psychology
25Gene mutations
26General & internal medicine
27Genetic
28Genetic aspects
29Genetic disorders
30Genetic Linkage
31Genetic research
32Genetic susceptibility
33Genetics
34Genetics & genetic processes
35Genetics of eukaryotes. Biological and molecular evolution
36Genetics(clinical)
37Genotype
38Genotype & phenotype
39Genotypes
40Génétique & processus génétiques
41Heredity
42Homozygote
43Human health sciences
44Humans
45Hypogammaglobulinemia
46Immune system
47Immunodeficiencies
48Immunodeficiencies. Immunoglobulinopathies
49Immunodeficiency
50Immunoglobulins
51Immunologic Deficiency Syndromes
52Immunologic Deficiency Syndromes - genetics
53Immunopathology
54Immunophenotyping
55Life sciences
56Linkage analysis
57Lipopolysaccharides
58Lymphocytes
59Lymphocytes B
60Male
61Medical genetics
62Medical sciences
63Medicin och hälsovetenskap
64Microscopy
65Microscopy, Electron, Transmission - methods
66Mitogens
67Models
68Models, Genetic
69Molecular and cellular biology
70Mutation
71Médecine générale & interne
72Pedigree
73Phagocytosis
74Phenotype
75Preschool
76Sciences de la santé humaine
77Sciences du vivant
78Signal Transducing
79Transmission
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1Tampella, Giacomo
2Pan-Hammarström, Qiang
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4Trujillo-Vargas, Claudia M
5Phadwal, Kanchan
6Simon, Anna Katharina
7Moutschen, Michel
8Etzioni, Amos
9Mory, Adi
10Srugo, Izhak
11Melamed, Doron
12Hultenby, Kjell
13Liu, Chonghai
14Baronio, Manuela
15Vitali, Massimiliano
16Philippet, Pierre
17Dideberg, Vinciane
18Aghamohammadi, Asghar
19Rezaei, Nima
20Enright, Victoria
21Du, Likun
22Salzer, Ulrich
23Eibel, Hermann
24Pfeifer, Dietmar
25Veelken, Hendrik
26Stauss, Hans
27Lougaris, Vassilios
28Plebani, Alessandro
29Gertz, E. Michael
30Schäffer, Alejandro A
31Hammarström, Lennart
32Grimbacher, Bodo
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titleDeleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity
authorLopez-Herrera, Gabriela ; Tampella, Giacomo ; Pan-Hammarström, Qiang ; Herholz, Peer ; Trujillo-Vargas, Claudia M ; Phadwal, Kanchan ; Simon, Anna Katharina ; Moutschen, Michel ; Etzioni, Amos ; Mory, Adi ; Srugo, Izhak ; Melamed, Doron ; Hultenby, Kjell ; Liu, Chonghai ; Baronio, Manuela ; Vitali, Massimiliano ; Philippet, Pierre ; Dideberg, Vinciane ; Aghamohammadi, Asghar ; Rezaei, Nima ; Enright, Victoria ; Du, Likun ; Salzer, Ulrich ; Eibel, Hermann ; Pfeifer, Dietmar ; Veelken, Hendrik ; Stauss, Hans ; Lougaris, Vassilios ; Plebani, Alessandro ; Gertz, E. Michael ; Schäffer, Alejandro A ; Hammarström, Lennart ; Grimbacher, Bodo
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0Adaptor Proteins
1Adaptor Proteins, Signal Transducing - genetics
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5Apoptosis
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7Autoimmune diseases
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15Cell Proliferation
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18Childrens health
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20Chromosome Mapping
21Development
22Electron
23Female
24Fundamental and applied biological sciences. Psychology
25Gene mutations
26General & internal medicine
27Genetic
28Genetic aspects
29Genetic disorders
30Genetic Linkage
31Genetic research
32Genetic susceptibility
33Genetics
34Genetics & genetic processes
35Genetics of eukaryotes. Biological and molecular evolution
36Genetics(clinical)
37Genotype
38Genotype & phenotype
39Genotypes
40Génétique & processus génétiques
41Heredity
42Homozygote
43Human health sciences
44Humans
45Hypogammaglobulinemia
46Immune system
47Immunodeficiencies
48Immunodeficiencies. Immunoglobulinopathies
49Immunodeficiency
50Immunoglobulins
51Immunologic Deficiency Syndromes
52Immunologic Deficiency Syndromes - genetics
53Immunopathology
54Immunophenotyping
55Life sciences
56Linkage analysis
57Lipopolysaccharides
58Lymphocytes
59Lymphocytes B
60Male
61Medical genetics
62Medical sciences
63Medicin och hälsovetenskap
64Microscopy
65Microscopy, Electron, Transmission - methods
66Mitogens
67Models
68Models, Genetic
69Molecular and cellular biology
70Mutation
71Médecine générale & interne
72Pedigree
73Phagocytosis
74Phenotype
75Preschool
76Sciences de la santé humaine
77Sciences du vivant
78Signal Transducing
79Transmission
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1Tampella, Giacomo
2Pan-Hammarström, Qiang
3Herholz, Peer
4Trujillo-Vargas, Claudia M
5Phadwal, Kanchan
6Simon, Anna Katharina
7Moutschen, Michel
8Etzioni, Amos
9Mory, Adi
10Srugo, Izhak
11Melamed, Doron
12Hultenby, Kjell
13Liu, Chonghai
14Baronio, Manuela
15Vitali, Massimiliano
16Philippet, Pierre
17Dideberg, Vinciane
18Aghamohammadi, Asghar
19Rezaei, Nima
20Enright, Victoria
21Du, Likun
22Salzer, Ulrich
23Eibel, Hermann
24Pfeifer, Dietmar
25Veelken, Hendrik
26Stauss, Hans
27Lougaris, Vassilios
28Plebani, Alessandro
29Gertz, E. Michael
30Schäffer, Alejandro A
31Hammarström, Lennart
32Grimbacher, Bodo
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15Environmental Sciences and Pollution Management
16Engineering Research Database
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jtitleAMERICAN JOURNAL OF HUMAN GENETICS
delivery
delcategoryRemote Search Resource
fulltextfulltext
addata
au
0Lopez-Herrera, Gabriela
1Tampella, Giacomo
2Pan-Hammarström, Qiang
3Herholz, Peer
4Trujillo-Vargas, Claudia M
5Phadwal, Kanchan
6Simon, Anna Katharina
7Moutschen, Michel
8Etzioni, Amos
9Mory, Adi
10Srugo, Izhak
11Melamed, Doron
12Hultenby, Kjell
13Liu, Chonghai
14Baronio, Manuela
15Vitali, Massimiliano
16Philippet, Pierre
17Dideberg, Vinciane
18Aghamohammadi, Asghar
19Rezaei, Nima
20Enright, Victoria
21Du, Likun
22Salzer, Ulrich
23Eibel, Hermann
24Pfeifer, Dietmar
25Veelken, Hendrik
26Stauss, Hans
27Lougaris, Vassilios
28Plebani, Alessandro
29Gertz, E. Michael
30Schäffer, Alejandro A
31Hammarström, Lennart
32Grimbacher, Bodo
formatjournal
genrearticle
ristypeJOUR
atitleDeleterious Mutations in LRBA Are Associated with a Syndrome of Immune Deficiency and Autoimmunity
jtitleAMERICAN JOURNAL OF HUMAN GENETICS
addtitleAm J Hum Genet
date2012-06-08
risdate2012
volume90
issue6
spage986
epage1001
pages986-1001
issn
00002-9297
11537-6605
eissn1537-6605
codenAJHGAG
notes
0scopus-id:84862132898
1These authors contributed equally to this work
abstractMost autosomal genetic causes of childhood-onset hypogammaglobulinemia are currently not well understood. Most affected individuals are simplex cases, but both autosomal-dominant and autosomal-recessive inheritance have been described. We performed genetic linkage analysis in consanguineous families affected by hypogammaglobulinemia. Four consanguineous families with childhood-onset humoral immune deficiency and features of autoimmunity shared genotype evidence for a linkage interval on chromosome 4q. Sequencing of positional candidate genes revealed that in each family, affected individuals had a distinct homozygous mutation in LRBA (lipopolysaccharide responsive beige-like anchor protein). All LRBA mutations segregated with the disease because homozygous individuals showed hypogammaglobulinemia and autoimmunity, whereas heterozygous individuals were healthy. These mutations were absent in healthy controls. Individuals with homozygous LRBA mutations had no LRBA, had disturbed B cell development, defective in vitro B cell activation, plasmablast formation, and immunoglobulin secretion, and had low proliferative responses. We conclude that mutations in LRBA cause an immune deficiency characterized by defects in B cell activation and autophagy and by susceptibility to apoptosis, all of which are associated with a clinical phenotype of hypogammaglobulinemia and autoimmunity.
copCambridge, MA
pubElsevier Inc
pmid22608502
doi10.1016/j.ajhg.2012.04.015
oafree_for_read