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1.
Nat Med ; 25(10): 1477-1487, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31548702

RESUMO

De novo and inherited rare genetic disorders (RGDs) are a major cause of human morbidity, frequently involving neuropsychiatric symptoms. Recent advances in genomic technologies and data sharing have revolutionized the identification and diagnosis of RGDs, presenting an opportunity to elucidate the mechanisms underlying neuropsychiatric disorders by investigating the pathophysiology of high-penetrance genetic risk factors. Here we seek out the best path forward for achieving these goals. We think future research will require consistent approaches across multiple RGDs and developmental stages, involving both the characterization of shared neuropsychiatric dimensions in humans and the identification of neurobiological commonalities in model systems. A coordinated and concerted effort across patients, families, researchers, clinicians and institutions, including rapid and broad sharing of data, is now needed to translate these discoveries into urgently needed therapies.

2.
Genet Med ; 21(11): 2413-2421, 2019 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-31182824

RESUMO

PURPOSE: For neurodevelopmental disorders (NDDs), etiological evaluation can be a diagnostic odyssey involving numerous genetic tests, underscoring the need to develop a streamlined algorithm maximizing molecular diagnostic yield for this clinical indication. Our objective was to compare the yield of exome sequencing (ES) with that of chromosomal microarray (CMA), the current first-tier test for NDDs. METHODS: We performed a PubMed scoping review and meta-analysis investigating the diagnostic yield of ES for NDDs as the basis of a consensus development conference. We defined NDD as global developmental delay, intellectual disability, and/or autism spectrum disorder. The consensus development conference included input from genetics professionals, pediatric neurologists, and developmental behavioral pediatricians. RESULTS: After applying strict inclusion/exclusion criteria, we identified 30 articles with data on molecular diagnostic yield in individuals with isolated NDD, or NDD plus associated conditions (such as Rett-like features). Yield of ES was 36% overall, 31% for isolated NDD, and 53% for the NDD plus associated conditions. ES yield for NDDs is markedly greater than previous studies of CMA (15-20%). CONCLUSION: Our review demonstrates that ES consistently outperforms CMA for evaluation of unexplained NDDs. We propose a diagnostic algorithm placing ES at the beginning of the evaluation of unexplained NDDs.

3.
Hum Mutat ; 39(11): 1614-1622, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30311389

RESUMO

Genome-scale sequencing creates vast amounts of genomic data, increasing the challenge of clinical sequence variant interpretation. The demand for high-quality interpretation requires multiple specialties to join forces to accelerate the interpretation of sequence variant pathogenicity. With over 600 international members including clinicians, researchers, and laboratory diagnosticians, the Clinical Genome Resource (ClinGen), funded by the National Institutes of Health, is forming expert groups to systematically evaluate variants in clinically relevant genes. Here, we describe the first ClinGen variant curation expert panels (VCEPs), development of consistent and streamlined processes for establishing new VCEPs, and creation of standard operating procedures for VCEPs to define application of the ACMG/AMP guidelines for sequence variant interpretation in specific genes or diseases. Additionally, ClinGen has created user interfaces to enhance reliability of curation and a Sequence Variant Interpretation Working Group (SVI WG) to harmonize guideline specifications and ensure consistency between groups. The expansion of VCEPs represents the primary mechanism by which curation of a substantial fraction of genomic variants can be accelerated and ultimately undertaken systematically and comprehensively. We welcome groups to utilize our resources and become involved in our effort to create a publicly accessible, centralized resource for clinically relevant genes and variants.

4.
Genet Med ; 2018 Sep 05.
Artigo em Inglês | MEDLINE | ID: mdl-30181607

RESUMO

The Clinical Genome Resource (ClinGen) is supported by the National Institutes of Health (NIH) to develop expertly curated and freely accessible resources defining the clinical relevance of genes and variants for use in precision medicine and research. To facilitate expert input, ClinGen has formed Clinical Domain Working Groups (CDWGs) to leverage the collective knowledge of clinicians, laboratory diagnosticians, and researchers. In the initial phase of ClinGen, CDWGs were launched in the cardiovascular, hereditary cancer, and inborn errors of metabolism clinical fields. These early CDWGs established the infrastructure necessary to implement standardized processes developed or adopted by ClinGen working groups for the interpretation of gene-disease associations and variant pathogenicity, and provided a sustainable model for the formation of future disease-focused curation groups. The establishment of CDWGs requires recruitment of international experts to broadly represent the interests of their field and ensure that assertions made are reliable and widely accepted. Building on the successes, challenges, and trade-offs made in establishing the original CDWGs, ClinGen has developed standard operating procedures for the development of CDWGs in new clinical domains, while maximizing efforts to scale up curation and facilitate involvement of external groups who wish to utilize ClinGen methods and infrastructure for expert curation.

5.
Hum Mutat ; 39(11): 1650-1659, 2018 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-30095202

RESUMO

Conflict resolution in genomic variant interpretation is a critical step toward improving patient care. Evaluating interpretation discrepancies in copy number variants (CNVs) typically involves assessing overlapping genomic content with focus on genes/regions that may be subject to dosage sensitivity (haploinsufficiency (HI) and/or triplosensitivity (TS)). CNVs containing dosage sensitive genes/regions are generally interpreted as "likely pathogenic" (LP) or "pathogenic" (P), and CNVs involving the same known dosage sensitive gene(s) should receive the same clinical interpretation. We compared the Clinical Genome Resource (ClinGen) Dosage Map, a publicly available resource documenting known HI and TS genes/regions, against germline, clinical CNV interpretations within the ClinVar database. We identified 251 CNVs overlapping known dosage sensitive genes/regions but not classified as LP or P; these were sent back to their original submitting laboratories for re-evaluation. Of 246 CNVs re-evaluated, an updated clinical classification was warranted in 157 cases (63.8%); no change was made to the current classification in 79 cases (32.1%); and 10 cases (4.1%) resulted in other types of updates to ClinVar records. This effort will add curated interpretation data into the public domain and allow laboratories to focus attention on more complex discrepancies.

6.
Health Aff (Millwood) ; 37(5): 757-764, 2018 05.
Artigo em Inglês | MEDLINE | ID: mdl-29733722

RESUMO

Health care delivery is increasingly influenced by the emerging concepts of precision health and the learning health care system. Although not synonymous with precision health, genomics is a key enabler of individualized care. Delivering patient-centered, genomics-informed care based on individual-level data in the current national landscape of health care delivery is a daunting challenge. Problems to overcome include data generation, analysis, storage, and transfer; knowledge management and representation for patients and providers at the point of care; process management; and outcomes definition, collection, and analysis. Development, testing, and implementation of a genomics-informed program requires multidisciplinary collaboration and building the concepts of precision health into a multilevel implementation framework. Using the principles of a learning health care system provides a promising solution. This article describes the implementation of population-based genomic medicine in an integrated learning health care system-a working example of a precision health program.

7.
Artigo em Inglês | MEDLINE | ID: mdl-29437798

RESUMO

Data sharing between laboratories, clinicians, researchers, and patients is essential for improvements and standardization in genomic medicine; encouraging genomic data sharing (GDS) is a key activity of the National Institutes of Health (NIH)-funded Clinical Genome Resource (ClinGen). The ClinGen initiative is dedicated to evaluating the clinical relevance of genes and variants for use in precision medicine and research. Currently, data originating from each of the aforementioned stakeholder groups is represented in ClinVar, a publicly available repository of genomic variation, and its relationship to human health hosted by the National Center for Biotechnology Information at the NIH. Although policies such as the 2014 NIH GDS policy are clear regarding the mandate for informed consent for broad data sharing from research participants, no clear guidance exists on the level of consent appropriate for the sharing of information obtained through clinical testing to advance knowledge. ClinGen has collaborated with ClinVar and the National Human Genome Research Institute to develop points to consider for clinical laboratories on sharing de-identified variant-level data in light of both the NIH GDS policy and the recent updates to the Common Rule. We propose specific data elements from interpreted genomic variants that are appropriate for submission to ClinVar when direct patient consent was not sought and describe situations in which obtaining informed consent is recommended.

8.
Genet Med ; 20(2): 169-171, 2018 02.
Artigo em Inglês | MEDLINE | ID: mdl-29323668

RESUMO

Disclaimer: This Points to Consider document is designed as an educational resource to provide best practices for medical genetic clinicians, laboratories, and journals regarding the provision, publication, and dissemination of patient phenotypes in the context of genomic testing, clinical genetic practice, and research. While the goal of the document is the improvement of patient care, the considerations and practices described should not be considered inclusive of all proper considerations and practices or exclusive of others that are reasonably directed to obtaining the same goal. In determining the value of any practice, clinicians, laboratories, and journals should apply their own professional standards and judgment to the specific circumstances presented.The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the authors' affiliated institutions.


Assuntos
Testes Genéticos/normas , Genética Médica/normas , Genômica/normas , Disseminação de Informação , Papel Profissional , Publicações/normas , Testes Genéticos/métodos , Genética Médica/métodos , Genômica/métodos , Humanos
10.
Am J Hum Genet ; 100(6): 895-906, 2017 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-28552198

RESUMO

With advances in genomic sequencing technology, the number of reported gene-disease relationships has rapidly expanded. However, the evidence supporting these claims varies widely, confounding accurate evaluation of genomic variation in a clinical setting. Despite the critical need to differentiate clinically valid relationships from less well-substantiated relationships, standard guidelines for such evaluation do not currently exist. The NIH-funded Clinical Genome Resource (ClinGen) has developed a framework to define and evaluate the clinical validity of gene-disease pairs across a variety of Mendelian disorders. In this manuscript we describe a proposed framework to evaluate relevant genetic and experimental evidence supporting or contradicting a gene-disease relationship and the subsequent validation of this framework using a set of representative gene-disease pairs. The framework provides a semiquantitative measurement for the strength of evidence of a gene-disease relationship that correlates to a qualitative classification: "Definitive," "Strong," "Moderate," "Limited," "No Reported Evidence," or "Conflicting Evidence." Within the ClinGen structure, classifications derived with this framework are reviewed and confirmed or adjusted based on clinical expertise of appropriate disease experts. Detailed guidance for utilizing this framework and access to the curation interface is available on our website. This evidence-based, systematic method to assess the strength of gene-disease relationships will facilitate more knowledgeable utilization of genomic variants in clinical and research settings.


Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença , Genômica , Humanos , Reprodutibilidade dos Testes
12.
Genet Med ; 19(5): 605, 2017 05.
Artigo em Inglês | MEDLINE | ID: mdl-28406491
13.
Genet Med ; 19(2): 249-255, 2017 02.
Artigo em Inglês | MEDLINE | ID: mdl-27854360

RESUMO

Disclaimer: These recommendations are designed primarily as an educational resource for medical geneticists and other healthcare providers to help them provide quality medical services. Adherence to these recommendations is completely voluntary and does not necessarily assure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedures and tests that are reasonably directed toward obtaining the same results. In determining the propriety of any specific procedure or test, the clinician should apply his or her own professional judgment to the specific clinical circumstances presented by the individual patient or specimen. Clinicians are encouraged to document the reasons for the use of a particular procedure or test, whether or not it is in conformance with this statement. Clinicians also are advised to take notice of the date this statement was adopted and to consider other medical and scientific information that becomes available after that date. It also would be prudent to consider whether intellectual property interests may restrict the performance of certain tests and other procedures.To promote standardized reporting of actionable information from clinical genomic sequencing, in 2013, the American College of Medical Genetics and Genomics (ACMG) published a minimum list of genes to be reported as incidental or secondary findings. The goal was to identify and manage risks for selected highly penetrant genetic disorders through established interventions aimed at preventing or significantly reducing morbidity and mortality. The ACMG subsequently established the Secondary Findings Maintenance Working Group to develop a process for curating and updating the list over time. We describe here the new process for accepting and evaluating nominations for updates to the secondary findings list. We also report outcomes from six nominations received in the initial 15 months after the process was implemented. Applying the new process while upholding the core principles of the original policy statement resulted in the addition of four genes and removal of one gene; one gene did not meet criteria for inclusion. The updated secondary findings minimum list includes 59 medically actionable genes recommended for return in clinical genomic sequencing. We discuss future areas of focus, encourage continued input from the medical community, and call for research on the impact of returning genomic secondary findings.Genet Med 19 2, 249-255.


Assuntos
Testes Genéticos/normas , Genética Médica/normas , Genoma Humano/genética , Sequenciamento Completo do Exoma , Exoma/genética , Genômica , Humanos
14.
Appl Clin Inform ; 7(3): 817-31, 2016 08 31.
Artigo em Inglês | MEDLINE | ID: mdl-27579472

RESUMO

BACKGROUND: The Clinical Genome Resource (ClinGen) Electronic Health Record (EHR) Workgroup aims to integrate ClinGen resources with EHRs. A promising option to enable this integration is through the Health Level Seven (HL7) Infobutton Standard. EHR systems that are certified according to the US Meaningful Use program provide HL7-compliant infobutton capabilities, which can be leveraged to support clinical decision-making in genomics. OBJECTIVES: To integrate genomic knowledge resources using the HL7 infobutton standard. Two tactics to achieve this objective were: (1) creating an HL7-compliant search interface for ClinGen, and (2) proposing guidance for genomic resources on achieving HL7 Infobutton standard accessibility and compliance. METHODS: We built a search interface utilizing OpenInfobutton, an open source reference implementation of the HL7 Infobutton standard. ClinGen resources were assessed for readiness towards HL7 compliance. Finally, based upon our experiences we provide recommendations for publishers seeking to achieve HL7 compliance. RESULTS: Eight genomic resources and two sub-resources were integrated with the ClinGen search engine via OpenInfobutton and the HL7 infobutton standard. Resources we assessed have varying levels of readiness towards HL7-compliance. Furthermore, we found that adoption of standard terminologies used by EHR systems is the main gap to achieve compliance. CONCLUSION: Genomic resources can be integrated with EHR systems via the HL7 Infobutton standard using OpenInfobutton. Full compliance of genomic resources with the Infobutton standard would further enhance interoperability with EHR systems.


Assuntos
Registros Eletrônicos de Saúde , Genômica , Interface Usuário-Computador , Mineração de Dados , Padrões de Referência , Ferramenta de Busca/normas
15.
J Autism Dev Disord ; 46(8): 2734-48, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-27207092

RESUMO

The 16p11.2 duplication (BP4-BP5) is associated with Autism Spectrum Disorder (ASD), although significant heterogeneity exists. Quantitative ASD, behavioral and neuropsychological measures and DSM-IV diagnoses in child and adult carriers were compared with familial non-carrier controls, and to published results from deletion carriers. The 16p11.2 duplication phenotype ranges widely from asymptomatic presentation to significant disability. The most common diagnoses were intellectual disability, motor delays and Attention Deficit Hyperactivity Disorder in children, and anxiety in adults. ASD occurred in nearly 20 % of child cases, but a majority of carriers did not show the unique social features of ASD. The 16p11.2 duplication phenotype is characterized by wider variability than the reciprocal deletion, likely reflecting contributions from additional risk factors.


Assuntos
Transtorno do Espectro Autista/genética , Transtorno do Espectro Autista/psicologia , Cromossomos Humanos Par 16/genética , Duplicação Gênica/genética , Adolescente , Adulto , Transtorno do Espectro Autista/diagnóstico , Transtorno Autístico/diagnóstico , Transtorno Autístico/genética , Transtorno Autístico/psicologia , Criança , Pré-Escolar , Deleção Cromossômica , Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Transtornos Cromossômicos/psicologia , Feminino , Humanos , Lactente , Deficiência Intelectual/diagnóstico , Deficiência Intelectual/genética , Deficiência Intelectual/psicologia , Masculino , Fenótipo
16.
Curr Protoc Hum Genet ; 89: 8.16.1-8.16.23, 2016 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-27037489

RESUMO

ClinVar is a freely accessible, public archive of reports of the relationships among genomic variants and phenotypes. To facilitate evaluation of the clinical significance of each variant, ClinVar aggregates submissions of the same variant, displays supporting data from each submission, and determines if the submitted clinical interpretations are conflicting or concordant. The unit describes how to (1) identify sequence and structural variants of interest in ClinVar by multiple searching approaches, including Variation Viewer and (2) understand the display of submissions to ClinVar and the evidence supporting each interpretation. By following this protocol, ClinVar users will be able to learn how to incorporate the wealth of resources and knowledge in ClinVar into variant curation and interpretation.


Assuntos
Bases de Dados Genéticas , Variação Genética , Genoma Humano , Humanos
17.
Genet Med ; 18(4): 341-9, 2016 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-26066539

RESUMO

PURPOSE: To characterize the clinical phenotype of the recurrent copy-number variation (CNV) at 1q21.1, we assessed the psychiatric and medical phenotypes of 1q21.1 deletion and duplication carriers ascertained through clinical genetic testing and family member cascade testing, with particular emphasis on dimensional assessment across multiple functional domains. METHODS: Nineteen individuals with 1q21.1 deletion, 19 individuals with the duplication, and 23 familial controls (noncarrier siblings and parents) spanning early childhood through adulthood were evaluated for psychiatric, neurologic, and other medical diagnoses, and their cognitive, adaptive, language, motor, and neurologic domains were also assessed. Twenty-eight individuals with 1q21.1 CNVs (15 deletion, 13 duplication) underwent structural magnetic resonance brain imaging. RESULTS: Probands with 1q21.1 CNVs presented with a range of psychiatric, neurologic, and medical disorders. Deletion and duplication carriers shared several features, including borderline cognitive functioning, impaired fine and gross motor functioning, articulation abnormalities, and hypotonia. Increased frequency of Autism Spectrum Disorder (ASD) diagnosis, increased ASD symptom severity, and increased prevalence of macrocephaly were observed in the duplication relative to deletion carriers, whereas reciprocally increased prevalence of microcephaly was observed in the deletion carriers. CONCLUSIONS: Individuals with 1q21.1 deletions or duplications exhibit consistent deficits on motor and cognitive functioning and abnormalities in head circumference.Genet Med 18 4, 341-349.


Assuntos
Transtornos Cromossômicos/diagnóstico , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 1 , Variações do Número de Cópias de DNA , Fenótipo , Adulto , Criança , Pré-Escolar , Deleção Cromossômica , Duplicação Cromossômica , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Testes Neuropsicológicos , Sistema de Registros , Adulto Jovem
18.
JAMA Psychiatry ; 72(2): 119-26, 2015 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-25493922

RESUMO

IMPORTANCE: Most disorders caused by copy number variants (CNVs) display significant clinical variability, often referred to as incomplete penetrance and variable expressivity. Genetic and environmental sources of this variability are not well understood. OBJECTIVES: To investigate the contributors to phenotypic variability in probands with CNVs involving the same genomic region; to measure the effect size for de novo mutation events; and to explore the contribution of familial background to resulting cognitive, behavioral, and motor performance outcomes in probands with de novo CNVs. DESIGN, SETTING, AND PARTICIPANTS: Family-based study design with a volunteer sample of 56 individuals with de novo 16p11.2 deletions and their noncarrier parents and siblings from the Simons Variation in Individuals Project. MAIN OUTCOMES AND MEASURES: We used linear mixed-model analysis to measure effect size and intraclass correlation to determine the influence of family background for a de novo CNV on quantitative traits representing the following 3 neurodevelopmental domains: cognitive ability (Full-Scale IQ), social behavior (Social Responsiveness Scale), and neuromotor performance (Purdue Pegboard Test). We included an anthropometric trait, body mass index, for comparison. RESULTS: A significant deleterious effect of the 16p11.2 deletion was demonstrated across all domains. Relative to the biparental mean, the effect sizes were -1.7 SD for cognitive ability, 2.2 SD for social behavior, and -1.3 SD for neuromotor performance (P < .001). Despite large deleterious effects, significant positive correlations between parents and probands were preserved for the Full-Scale IQ (0.42 [P = .03]), the verbal IQ (0.53 [P = .004]), and the Social Responsiveness Scale (0.52 [P = .009]) scores. We also observed a 1-SD increase in the body mass index of probands compared with siblings, with an intraclass correlation of 0.40 (P = .07). CONCLUSIONS AND RELEVANCE: Analysis of families with de novo CNVs provides the least confounded estimate of the effect size of the 16p11.2 deletion on heritable, quantitative traits and demonstrates a 1- to 2-SD effect across all neurodevelopmental dimensions. Significant parent-proband correlations indicate that family background contributes to the phenotypic variability seen in this and perhaps other CNV disorders and may have implications for counseling families regarding their children's developmental and psychiatric prognoses. Use of biparental mean scores rather than general population mean scores may be more relevant to examine the effect of a mutation or any other cause of trait variation on a neurodevelopmental outcome and possibly on systems of diagnosis and trait ascertainment for developmental disorders.


Assuntos
Transtorno Autístico/fisiopatologia , Transtornos Cromossômicos/fisiopatologia , Deficiência Intelectual/fisiopatologia , Inteligência/genética , Pais , Fenótipo , Desempenho Psicomotor/fisiologia , Comportamento Social , Adulto , Transtorno Autístico/genética , Deleção Cromossômica , Transtornos Cromossômicos/genética , Cromossomos Humanos Par 16/genética , Variações do Número de Cópias de DNA/genética , Feminino , Humanos , Deficiência Intelectual/genética , Masculino , Irmãos
19.
Biol Psychiatry ; 77(9): 785-93, 2015 May 01.
Artigo em Inglês | MEDLINE | ID: mdl-25064419

RESUMO

BACKGROUND: Deletion of the recurrent ~600 kb BP4-BP5 chromosomal region 16p11.2 has been associated with a wide range of neurodevelopmental outcomes. METHODS: To clarify the phenotype of 16p11.2 deletion, we examined the psychiatric and developmental presentation of predominantly clinically referred individuals, with a particular emphasis on broader autism phenotype characteristics in individuals with recurrent ~600 kb chromosome 16p11.2 deletions. Using an extensive standardized assessment battery across three clinical sites, 85 individuals with the 16p11.2 deletion and 153 familial control subjects were evaluated for symptom presentation and clinical diagnosis. RESULTS: Individuals with the 16p11.2 deletion presented with a high frequency of psychiatric and developmental disorders (>90%). The most commonly diagnosed conditions were developmental coordination disorder, phonologic processing disorder, expressive and receptive language disorders (71% of individuals >3 years old with a speech and language-related disorder), and autism spectrum disorder. Individuals with the 16p11.2 deletion not meeting diagnostic criteria for autism spectrum disorder had a significantly higher prevalence of autism-related characteristics compared with the familial noncarrier control group. Individuals with the 16p11.2 deletion had a range of intellectual ability, but IQ scores were 26 points lower than noncarrier family members on average. CONCLUSIONS: Clinically referred individuals with the 16p11.2 deletion have high rates of psychiatric and developmental disorders and provide a genetically well-defined group to study the emergence of developmental difficulties, particularly associated with the broader autism phenotype.


Assuntos
Deleção Cromossômica , Cromossomos Humanos Par 16 , Cognição , Deficiências do Desenvolvimento/genética , Transtornos Mentais/genética , Fenótipo , Adolescente , Criança , Pré-Escolar , Deficiências do Desenvolvimento/fisiopatologia , Deficiências do Desenvolvimento/psicologia , Heterozigoto , Humanos , Inteligência/genética , Transtornos Mentais/fisiopatologia , Transtornos Mentais/psicologia , Adulto Jovem
20.
Biochem Biophys Res Commun ; 451(1): 48-53, 2014 Aug 15.
Artigo em Inglês | MEDLINE | ID: mdl-25035924

RESUMO

The invariant chain (CD74) mediates targeting of the MHCII complex to endosomal compartments, where CD74 undergoes degradation allowing MHCII to acquire peptides. We demonstrated recently that intramembrane proteolysis of the final membrane-bound N-terminal fragment (NTF) of CD74 is catalyzed by Signal-peptide-peptidase-like 2a (SPPL2a) and that this process is indispensable for development and function of B lymphocytes in mice. In SPPL2a(-/-) mice, homeostasis of these cells is disturbed by the accumulation of the unprocessed CD74 NTF. So far, evidence for this essential role of SPPL2a is restricted to mice. Nevertheless, inhibition of SPPL2a has been suggested as novel approach to target B cells for treating autoimmunity. Here, we characterize human B cell lines with a homozygous microdeletion on chromosome 15. We demonstrate that this deletion disrupts the SPPL2a genomic locus and leads to loss of SPPL2a transcript. Lymphoblastoid cell lines from patients with this deletion exhibit absence of SPPL2a at the protein level and show an accumulation of the CD74 NTF comparable to B cells from SPPL2a(-/-) mice. By this means, we present evidence that the role of SPPL2a in CD74 proteolysis is conserved in human B cells and provide support for modulation of SPPL2a activity as a therapeutic concept.


Assuntos
Antígenos de Diferenciação de Linfócitos B/metabolismo , Ácido Aspártico Endopeptidases/metabolismo , Linfócitos B/metabolismo , Cromossomos Humanos Par 15 , Antígenos de Histocompatibilidade Classe II/metabolismo , Antígenos de Diferenciação de Linfócitos B/genética , Ácido Aspártico Endopeptidases/genética , Linfócitos B/patologia , Linhagem Celular , Deleção Cromossômica , Antígenos de Histocompatibilidade Classe II/genética , Homozigoto , Humanos , Síndromes de Imunodeficiência/genética , Membranas Intracelulares/metabolismo , Fragmentos de Peptídeos/genética , Fragmentos de Peptídeos/metabolismo
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