Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency
Mutations in the tetratricopeptide repeat domain 7A (TTC7A) gene cause very early onset inflammatory bowel diseases (VOIBD) or multiple intestinal atresia associated with immune deficiency of various severities, ranging from combined immune deficiency to mild lymphopenia. In this manuscript, we repo...
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| Format: | Article |
| Language: | English |
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Frontiers Media S.A.
2019-11-01
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| Series: | Frontiers in Immunology |
| Subjects: | |
| Online Access: | https://www.frontiersin.org/article/10.3389/fimmu.2019.02592/full |
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doaj-2eee4e6109d1419e85a9d7180c1803fa |
|---|---|
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Article |
| collection |
DOAJ |
| language |
English |
| format |
Article |
| sources |
DOAJ |
| author |
Marie-Thérèse El-Daher Marie-Thérèse El-Daher Julie Lemale Julie Bruneau Julie Bruneau Claire Leveau Claire Leveau Frédéric Guerin Frédéric Guerin Nathalie Lambert Jean-Sébastien Diana Bénédicte Neven Fernando E. Sepulveda Fernando E. Sepulveda Fernando E. Sepulveda Aurore Coulomb-L'Hermine Thierry Molina Thierry Molina Capucine Picard Capucine Picard Capucine Picard Alain Fischer Alain Fischer Alain Fischer Geneviève de Saint Basile Geneviève de Saint Basile Geneviève de Saint Basile |
| spellingShingle |
Marie-Thérèse El-Daher Marie-Thérèse El-Daher Julie Lemale Julie Bruneau Julie Bruneau Claire Leveau Claire Leveau Frédéric Guerin Frédéric Guerin Nathalie Lambert Jean-Sébastien Diana Bénédicte Neven Fernando E. Sepulveda Fernando E. Sepulveda Fernando E. Sepulveda Aurore Coulomb-L'Hermine Thierry Molina Thierry Molina Capucine Picard Capucine Picard Capucine Picard Alain Fischer Alain Fischer Alain Fischer Geneviève de Saint Basile Geneviève de Saint Basile Geneviève de Saint Basile Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency Frontiers in Immunology tetratricopeptide repeat domain 7A lymphoproliferative syndrome intestinal pseudo-obstruction fsn mouse mutant's cell phenotype |
| author_facet |
Marie-Thérèse El-Daher Marie-Thérèse El-Daher Julie Lemale Julie Bruneau Julie Bruneau Claire Leveau Claire Leveau Frédéric Guerin Frédéric Guerin Nathalie Lambert Jean-Sébastien Diana Bénédicte Neven Fernando E. Sepulveda Fernando E. Sepulveda Fernando E. Sepulveda Aurore Coulomb-L'Hermine Thierry Molina Thierry Molina Capucine Picard Capucine Picard Capucine Picard Alain Fischer Alain Fischer Alain Fischer Geneviève de Saint Basile Geneviève de Saint Basile Geneviève de Saint Basile |
| author_sort |
Marie-Thérèse El-Daher |
| title |
Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency |
| title_short |
Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency |
| title_full |
Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency |
| title_fullStr |
Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency |
| title_full_unstemmed |
Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A Deficiency |
| title_sort |
chronic intestinal pseudo-obstruction and lymphoproliferative syndrome as a novel phenotype associated with tetratricopeptide repeat domain 7a deficiency |
| publisher |
Frontiers Media S.A. |
| series |
Frontiers in Immunology |
| issn |
1664-3224 |
| publishDate |
2019-11-01 |
| description |
Mutations in the tetratricopeptide repeat domain 7A (TTC7A) gene cause very early onset inflammatory bowel diseases (VOIBD) or multiple intestinal atresia associated with immune deficiency of various severities, ranging from combined immune deficiency to mild lymphopenia. In this manuscript, we report the clinical, biological and molecular features of a patient born from consanguineous parents, presenting with recurrent lymphoproliferative syndrome and pan-hypergammaglobulinemia associated with chronic intestinal pseudo obstruction (CIPO). Genetic screening revealed the novel c.974G>A (p.R325Q) mutation in homozygosity in the TTC7A gene. The patient's phenotype differs significantly from that previously associated with TTC7A deficiency in humans. It becomes closer to the one reported in the ttc7a-deficient mice that invariably develop a proliferative lymphoid and myeloid disorder. Functional studies showed that the extreme variability in the clinical phenotype couldn't be explained by the cellular phenotype. Indeed, the patient's TTC7A mutation, as well as the murine-ttc7 mutant, have the same functional impact on protein expression, DNA instability and chromatin compaction, as the other mutations that lead to classical TTC7A-associated phenotypes. Co-inheritance of genetic variants may also contribute to the unique nature of the patient's phenotype. The present case report shows that the clinical spectrum of TTC7A deficiency is much broader than previously suspected. Our findings should alert the physicians to consider screening of TTC7A mutations in patients with lymphoproliferative syndrome and hypergammaglobulinemia and/or chronic intestinal pseudo-obstruction. |
| topic |
tetratricopeptide repeat domain 7A lymphoproliferative syndrome intestinal pseudo-obstruction fsn mouse mutant's cell phenotype |
| url |
https://www.frontiersin.org/article/10.3389/fimmu.2019.02592/full |
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doaj-2eee4e6109d1419e85a9d7180c1803fa2020-11-25T01:36:18ZengFrontiers Media S.A.Frontiers in Immunology1664-32242019-11-011010.3389/fimmu.2019.02592497941Chronic Intestinal Pseudo-Obstruction and Lymphoproliferative Syndrome as a Novel Phenotype Associated With Tetratricopeptide Repeat Domain 7A DeficiencyMarie-Thérèse El-Daher0Marie-Thérèse El-Daher1Julie Lemale2Julie Bruneau3Julie Bruneau4Claire Leveau5Claire Leveau6Frédéric Guerin7Frédéric Guerin8Nathalie Lambert9Jean-Sébastien Diana10Bénédicte Neven11Fernando E. Sepulveda12Fernando E. Sepulveda13Fernando E. Sepulveda14Aurore Coulomb-L'Hermine15Thierry Molina16Thierry Molina17Capucine Picard18Capucine Picard19Capucine Picard20Alain Fischer21Alain Fischer22Alain Fischer23Geneviève de Saint Basile24Geneviève de Saint Basile25Geneviève de Saint Basile26Laboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Paris, FranceImagine Institute, Université de Paris, Paris, FrancePediatric Nutrition and Gastroenterology Department, Trousseau Hospital, Assistance Publique-Hôpitaux de Paris, Sorbonne Université, Paris, FranceImagine Institute, Université de Paris, Paris, FranceDepartment of Pathology, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, FranceLaboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Paris, FranceImagine Institute, Université de Paris, Paris, FranceLaboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Paris, FranceImagine Institute, Université de Paris, Paris, FranceCenter for the Study of Primary Immunodeficiencies, Necker Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris, Paris, FrancePediatric Hematology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM UMR 1163, Paris, FrancePediatric Hematology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM UMR 1163, Paris, FranceLaboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Paris, FranceImagine Institute, Université de Paris, Paris, FranceCentre Nationale de la Recherche Scientifique – CNRS, Villejuif, FranceDepartment of Pathology, Hôpital A Trousseau, Assistance-Publique des Hôpitaux de Paris, Sorbonne Université, Paris, FranceImagine Institute, Université de Paris, Paris, FranceDepartment of Pathology, Hôpital Necker-Enfants Malades, Assistance Publique des Hôpitaux de Paris, Paris, FranceImagine Institute, Université de Paris, Paris, FranceCenter for the Study of Primary Immunodeficiencies, Necker Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris, Paris, FranceLaboratory of Lymphocyte Activation and Susceptibility to EBV Infection, INSERM UMR 1163, Paris, FranceImagine Institute, Université de Paris, Paris, FrancePediatric Hematology Department, Hôpital Necker-Enfants Malades, Assistance Publique-Hôpitaux de Paris, Paris, France; INSERM UMR 1163, Paris, France0Collège de France, Paris, FranceLaboratory of Normal and Pathological Homeostasis of the Immune System, INSERM UMR 1163, Paris, FranceImagine Institute, Université de Paris, Paris, FranceCenter for the Study of Primary Immunodeficiencies, Necker Enfants Malades Hospital, Assistance Publique des Hôpitaux de Paris, Paris, FranceMutations in the tetratricopeptide repeat domain 7A (TTC7A) gene cause very early onset inflammatory bowel diseases (VOIBD) or multiple intestinal atresia associated with immune deficiency of various severities, ranging from combined immune deficiency to mild lymphopenia. In this manuscript, we report the clinical, biological and molecular features of a patient born from consanguineous parents, presenting with recurrent lymphoproliferative syndrome and pan-hypergammaglobulinemia associated with chronic intestinal pseudo obstruction (CIPO). Genetic screening revealed the novel c.974G>A (p.R325Q) mutation in homozygosity in the TTC7A gene. The patient's phenotype differs significantly from that previously associated with TTC7A deficiency in humans. It becomes closer to the one reported in the ttc7a-deficient mice that invariably develop a proliferative lymphoid and myeloid disorder. Functional studies showed that the extreme variability in the clinical phenotype couldn't be explained by the cellular phenotype. Indeed, the patient's TTC7A mutation, as well as the murine-ttc7 mutant, have the same functional impact on protein expression, DNA instability and chromatin compaction, as the other mutations that lead to classical TTC7A-associated phenotypes. Co-inheritance of genetic variants may also contribute to the unique nature of the patient's phenotype. The present case report shows that the clinical spectrum of TTC7A deficiency is much broader than previously suspected. Our findings should alert the physicians to consider screening of TTC7A mutations in patients with lymphoproliferative syndrome and hypergammaglobulinemia and/or chronic intestinal pseudo-obstruction.https://www.frontiersin.org/article/10.3389/fimmu.2019.02592/fulltetratricopeptide repeat domain 7Alymphoproliferative syndromeintestinal pseudo-obstructionfsn mousemutant's cell phenotype |