Rare splicing defects of FAS underly severe recessive autoimmune lymphoproliferative syndrome

Agrebi, Nourhen; Ben‐Mustapha, Imen; Matoussi, N.; Dhouib, Naouel Guirat; Ben-Ali, Meriem; Mekki, Najla; Ahmed, Mélika Ben; Larguèche, Beya; Bêcher, S. Ben; Béjaoui, Mohamed; Barbouche, Mohamed‐Ridha

doi:10.1016/j.clim.2017.06.009

Cited by 20 publications

(19 citation statements)

References 34 publications

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“…These mechanisms fit well with outbred human populations . In contrast, in our consanguineous settings, we have now identified 4 different FAS homozygous mutations including those with preserved or absent Fas protein expression, while we identified only 3 heterozygous ALPS patients so far …”

Section: Novel Form Of Ar Alps‐fas With Normal or Residual Protein Exsupporting

confidence: 77%

“…These mechanisms fit well with outbred human populations. 45 In contrast, in our consanguineous settings, we have now identified 4 different FAS homozygous mutations including those with preserved or absent Fas protein expression, 17,46 while we identified only 3 heterozygous ALPS patients so far. 2 This novel AR mode of inheritance of ALPS-FAS with normal or decreased protein expression is definitely favored by the consanguineous environment.…”

Section: Novel Form Of Ar Alps-fas With Normal or Residual Protein Exmentioning

confidence: 65%

“…Indeed, both patients present 2 novel FAS gene mutations resulting in defective splicing and the skipping of exon 6, which encodes the transmembrane domain of CD95, thus precluding normal Fas expression. Interestingly, only the truncated form of Fas was found in these patients …”

Section: Homozygous Fas Exon 6 Splicing Defects Underlying Alps‐fas Amentioning

confidence: 87%

“…Interestingly, only the truncated form of Fas was found in these patients. 17 The first mutation (c.506-16A > G) was predicted to break a potential branch point sequence (BPS) inducing aberrant splicing. Indeed, it affects a highly conserved adenosine "A" that acts as the nucleophile in the first catalytic step of splicing 32 and is bound by the splicing factor 1 (SF1).…”

Section: Homozygous Fas Exon 6 Splicing Defects Underlying Alps-fas Amentioning

confidence: 99%

“…Nevertheless, the J Leukoc Biol. 2018;103:501-508. c 2017 Society for Leukocyte Biology 501 www.jleukbio.org majority of patients have mutations in the FAS (TNFRSF6/APO1/CD95) gene that could be either: (1) germline heterozygous, inherited in an autosomal dominant (AD) pattern and associated with preserved protein expression, 12 (2) germline homozygous, inherited in an AR pattern with lack of protein expression, [13][14][15][16][17] or (3) somatic, detected primarily in DNT cells. 9 Other genes than FAS could be involved including mutations in the gene encoding FasL (ALPS-FASLG) or caspase-10 (ALPS-CASP10), which have been identified in a minority of patients.…”

Section: Introductionmentioning

confidence: 99%

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Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

Ben‐Mustapha

Agrebi

Barbouche

2017

Journal of Leukocyte Biology

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Autoimmune lymphoproliferative syndrome (ALPS) is a primary immunodeficiency disease due to impaired Fas-Fas ligand apoptotic pathway. It is characterized by chronic nonmalignant, noninfectious lymphadenopathy and/or splenomegaly associated with autoimmune manifestations primarily directed against blood cells. Herein, we review the heterogeneous ALPS molecular bases and discuss recent findings revealed by the study of consanguineous patients. Indeed, this peculiar genetic background favored the identification of a novel form of AR ALPS-FAS associated with normal or residual protein expression, expanding the spectrum of ALPS types. In addition, rare mutational mechanisms underlying the splicing defects of FAS exon 6 have been identified in AR ALPS-FAS with lack of protein expression. These findings will help decipher critical regions required for the tight regulation of FAS exon 6 splicing. We also discuss the genotype-phenotype correlation and disease severity in AR ALPS-FAS. Altogether, the study of ALPS molecular bases in endogamous populations helps to better classify the disease subgroups and to unravel the Fas pathway functioning.

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Section: Novel Form Of Ar Alps‐fas With Normal or Residual Protein Exsupporting

confidence: 77%

Section: Novel Form Of Ar Alps-fas With Normal or Residual Protein Exmentioning

confidence: 65%

Section: Homozygous Fas Exon 6 Splicing Defects Underlying Alps‐fas Amentioning

confidence: 87%

Section: Homozygous Fas Exon 6 Splicing Defects Underlying Alps-fas Amentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

Ben‐Mustapha

Agrebi

Barbouche

2017

Journal of Leukocyte Biology

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Genetic Testing in Patients with Autoimmune Lymphoproliferative Syndrome: Experience of 802 Patients at Cincinnati Children’s Hospital Medical Center

Xu,

Denton,

et al. 2024

J Clin Immunol

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Autoimmune lymphoproliferative syndrome (ALPS) is a rare genetic disorder featuring chronic lymphadenopathy, splenomegaly, cytopenias, and increased lymphoma risk. Differentiating ALPS from immunodeficiencies with overlapping symptoms is challenging. This study evaluated the performance and the diagnostic yield of a 15-gene NGS panel for ALPS at Cincinnati Children’s Hospital Medical Center. Samples from 802 patients submitted for ALPS NGS panel were studied between May 2014 and January 2023. A total of 62 patients (7.7%) had a definite diagnosis: 52/62 cases (84%) showed 37 unique pathogenic/likely pathogenic germline FAS variants supporting ALPS diagnosis (6.5%, 52/802). The ALPS diagnostic yield increased to 30% in patients who additionally fulfilled abnormal ALPS immunology findings criteria. 17/37 (46%) diagnostic FAS variants were novel variants reported for the first time in ALPS. 10/802 cases (1.2%) showed diagnostic findings in five genes (ADA2, CTLA4, KRAS, MAGT1, NRAS) which are related to autoimmune lymphoproliferative immunodeficiency (ALPID). Family studies enabled the reclassification of variants of unknown significance (VUS) and also the identification of at-risk family members of FAS-positive patients, which helped in the follow-up diagnosis and treatment. Alongside family studies, complete clinical phenotypes and abnormal ALPS immunology and Fas-mediated apoptosis results helped clarify uncertain genetic findings. This study describes the largest cohort of genetic testing for suspected ALPS in North America and highlights the effectiveness of the ALPS NGS panel in distinguishing ALPS from non-ALPS immunodeficiencies. More comprehensive assessment from exome or genome sequencing could be considered for undefined ALPS-U patients or non-ALPS immunodeficiencies after weighing cost, completeness, and timeliness of different genetic testing options.

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Managing Lupus Nephritis in Children and Adolescents

Chan,

Lai,

et al. 2023

Pediatr Drugs

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Rare splicing defects of FAS underly severe recessive autoimmune lymphoproliferative syndrome

Cited by 20 publications

References 34 publications

Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

Novel insights into FAS defects underlying autoimmune lymphoproliferative syndrome revealed by studies in consanguineous patients

Genetic Testing in Patients with Autoimmune Lymphoproliferative Syndrome: Experience of 802 Patients at Cincinnati Children’s Hospital Medical Center

Managing Lupus Nephritis in Children and Adolescents

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