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1.
Hum Reprod ; 38(5): 992-1002, 2023 05 02.
Artículo en Inglés | MEDLINE | ID: mdl-36952633

RESUMEN

STUDY QUESTION: Does mitochondrial deficiency affect human embryonic preimplantation development? SUMMARY ANSWER: The presence of a pathogenic mitochondrial variant triggers changes in the gene expression of preimplantation human embryos, compromising their development, cell differentiation, and survival. WHAT IS KNOWN ALREADY: Quantitative and qualitative anomalies of mitochondrial DNA (mtDNA) are reportedly associated with impaired human embryonic development, but the underlying mechanisms remain unexplained. STUDY DESIGN, SIZE, DURATION: Taking advantage of the preimplantation genetic testing for mitochondrial disorders in at-risk couples, we have compared gene expression of 9 human embryos carrying pathogenic variants in either mtDNA genes or nuclear genes encoding mitochondrial protein to 33 age-matched control embryos. PARTICIPANTS/MATERIALS, SETTING, METHODS: Single-embryo transcriptomic analysis was performed on whole human blastocyst embryos donated to research. MAIN RESULTS AND THE ROLE OF CHANCE: Specific pathogenic mitochondrial variants downregulate gene expression in preimplantation human embryos [566 genes in oxidative phosphorylation (OXPHOS)-deficient embryos], impacting transcriptional regulators, differentiation factors, and nuclear genes encoding mitochondrial proteins. These changes in gene expression primarily alter OXPHOS and cell survival pathways. LIMITATIONS, REASONS FOR CAUTION: The number of OXPHOS-deficient embryos available for the study was limited owing to the rarity of this material. However, the molecular signature shared by all these embryos supports the relevance of the findings. WIDER IMPLICATIONS OF THE FINDINGS: While identification of reliable markers of normal embryonic development is urgently needed in ART, our study prompts us to consider under-expression of the targeted genes reported here, as predictive biomarkers of mitochondrial dysfunction during preimplantation development. STUDY FUNDING/COMPETING INTEREST(S): This work was supported by the 'Association Française contre les Myopathies (AFM-Téléthon)' and the 'La Fondation Maladies Rares'. No competing interests to declare. TRIAL REGISTRATION NUMBER: N/A.


Asunto(s)
Embrión de Mamíferos , Enfermedades Mitocondriales , Embarazo , Femenino , Humanos , Embrión de Mamíferos/metabolismo , Desarrollo Embrionario/genética , ADN Mitocondrial/genética , Blastocisto/metabolismo , Expresión Génica
2.
Am J Med Genet A ; 191(12): 2813-2818, 2023 12.
Artículo en Inglés | MEDLINE | ID: mdl-37533297

RESUMEN

Waardenburg syndrome (WS) is characterized by the association of sensorineural hearing loss and pigmentation abnormalities. Among the four types, WS Type 2 (WS2) is the only one without a remarkable distinguishing feature. Here, we report a patient initially diagnosed with WS2 who exhibits a 446 kb mosaic duplication in chromosome 22q13.1, encompassing SOX10, and detected using whole genome sequencing in a trio. The patient, a 46,XY boy, presents with profound bilateral sensorineural hearing loss, right heterochromia iridium, left bright blue iris, and skin-depigmented areas in the abdomen and limbs. Vestibular and imaging tests are normal, without inner ear or olfactory bulb malformations. Bilateral cochlear implantation did not prevent language and speech delays. Moderate congenital chronic constipation and neurodevelopmental difficulties were also present. Given the few genes included in this duplicated region (only one OMIM gene with dominant inheritance), this report provides further delineation of the phenotype related to duplications encompassing the entire SOX10 gene.


Asunto(s)
Pérdida Auditiva Sensorineural , Vestíbulo del Laberinto , Síndrome de Waardenburg , Masculino , Humanos , Mosaicismo , Fenotipo , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , Síndrome de Waardenburg/diagnóstico , Síndrome de Waardenburg/genética , Factores de Transcripción SOXE/genética , Mutación
3.
J Allergy Clin Immunol ; 149(4): 1358-1372, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-34543653

RESUMEN

BACKGROUND: Netherton syndrome (NS) is a rare recessive skin disorder caused by loss-of-function mutations in SPINK5 encoding the protease inhibitor LEKTI (lymphoepithelial Kazal-type-related inhibitor). NS patients experience severe skin barrier defects, display inflammatory skin lesions, and have superficial scaling with atopic manifestations. They present with typical ichthyosis linearis circumflexa (NS-ILC) or scaly erythroderma (NS-SE). OBJECTIVE: We used a combination of several molecular profiling methods to comprehensively characterize the skin, immune cells, and allergic phenotypes of NS-ILC and NS-SE patients. METHODS: We studied a cohort of 13 patients comprising 9 NS-ILC and 4 NS-SE. RESULTS: Integrated multiomics revealed abnormal epidermal proliferation and differentiation and IL-17/IL-36 signatures in lesion skin and in blood in both NS endotypes. Although the molecular profiles of NS-ILC and NS-SE lesion skin were very similar, nonlesion skin of each disease subtype displayed distinctive molecular features. Nonlesion and lesion NS-SE epidermis showed activation of the type I IFN signaling pathway, while lesion NS-ILC skin differed from nonlesion NS-ILC skin by increased complement activation and neutrophil infiltration. Serum cytokine profiling and immunophenotyping of circulating lymphocytes showed a TH2-driven allergic response in NS-ILC, whereas NS-SE patients displayed mainly a TH9 axis with increased CCL22/MDC and CCL17/TARC serum levels. CONCLUSIONS: This study confirms IL-17/IL-36 as the predominant signaling axes in both NS endotypes and unveils molecular features distinguishing NS-ILC and NS-SE. These results identify new therapeutic targets and could pave the way for precision medicine of NS.


Asunto(s)
Hipersensibilidad , Síndrome de Netherton , Enfermedades de la Piel , Epidermis/patología , Humanos , Hipersensibilidad/patología , Interferón-alfa , Interleucina-17/genética , Síndrome de Netherton/genética , Proteínas Inhibidoras de Proteinasas Secretoras/genética , Inhibidor de Serinpeptidasas Tipo Kazal-5/genética , Piel/patología , Enfermedades de la Piel/patología
4.
J Clin Immunol ; 42(3): 559-571, 2022 04.
Artículo en Inglés | MEDLINE | ID: mdl-35000057

RESUMEN

PURPOSE: X-linked inhibitor of apoptosis protein (XIAP) deficiency, also known as the X-linked lymphoproliferative syndrome of type 2 (XLP-2), is a rare immunodeficiency characterized by recurrent hemophagocytic lymphohistiocytosis, splenomegaly, and inflammatory bowel disease. Variants in XIAP including missense, non-sense, frameshift, and deletions of coding exons have been reported to cause XIAP deficiency. We studied three young boys with immunodeficiency displaying XLP-2-like clinical features. No genetic variation in the coding exons of XIAP was identified by whole-exome sequencing (WES), although the patients exhibited a complete loss of XIAP expression. METHODS: Targeted next-generation sequencing (NGS) of the entire locus of XIAP was performed on DNA samples from the three patients. Molecular investigations were assessed by gene reporter expression assays in HEK cells and CRISPR-Cas9 genome editing in primary T cells. RESULTS: NGS of XIAP identified three distinct non-coding deletions in the patients that were predicted to be driven by repetitive DNA sequences. These deletions share a common region of 839 bp that encompassed the first non-coding exon of XIAP and contained regulatory elements and marks specific of an active promoter. Moreover, we showed that among the 839 bp, the exon was transcriptionally active. Finally, deletion of the exon by CRISPR-Cas9 in primary cells reduced XIAP protein expression. CONCLUSIONS: These results identify a key promoter sequence contained in the first non-coding exon of XIAP. Importantly, this study highlights that sequencing of the non-coding exons that are not currently captured by WES should be considered in the genetic diagnosis when no variation is found in coding exons.


Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X , Trastornos Linfoproliferativos , Enfermedades Genéticas Ligadas al Cromosoma X/diagnóstico , Enfermedades Genéticas Ligadas al Cromosoma X/genética , Células Germinativas/metabolismo , Humanos , Trastornos Linfoproliferativos/diagnóstico , Trastornos Linfoproliferativos/genética , Trastornos Linfoproliferativos/metabolismo , Masculino , Proteína Inhibidora de la Apoptosis Ligada a X
5.
Hum Reprod ; 37(12): 2952-2959, 2022 11 24.
Artículo en Inglés | MEDLINE | ID: mdl-36331510

RESUMEN

STUDY QUESTION: Can mutations of genes other than AMH or AMHR2, namely PPP1R12A coding myosin phosphatase, lead to persistent Müllerian duct syndrome (PMDS)? SUMMARY ANSWER: The detection of PPP1R12A truncation mutations in five cases of PMDS suggests that myosin phosphatase is involved in Müllerian regression, independently of the anti-Müllerian hormone (AMH) signaling cascade. WHAT IS KNOWN ALREADY: Mutations of AMH and AMHR2 are detectable in an overwhelming majority of PMDS patients but in 10% of cases, both genes are apparently normal, suggesting that other genes may be involved. STUDY DESIGN, SIZE, DURATION: DNA samples from 39 PMDS patients collected from 1990 to present, in which Sanger sequencing had failed to detect biallelic AMH or AMHR2 mutations, were screened by massive parallel sequencing. PARTICIPANTS/MATERIALS, SETTING, METHODS: To rule out the possibility that AMH or AMHR2 mutations could have been missed, all DNA samples of good quality were analyzed by targeted next-generation sequencing. Twenty-four samples in which the absence of AMH or AMHR2 biallelic mutations was confirmed were subjected to whole-exome sequencing with the aim of detecting variants of other genes potentially involved in PMDS. MAIN RESULTS AND THE ROLE OF CHANCE: Five patients out of 24 (21%) harbored deleterious truncation mutations of PP1R12A, the gene coding for the regulatory subunit of myosin phosphatase, were detected. In addition to PMDS, three of these patients presented with ileal and one with esophageal atresia. The congenital abnormalities associated with PMDS in our patients are consistent with those described in the literature for PPP1R12A variants and have never been described in cases of AMH or AMHR2 mutations. The role of chance is therefore extremely unlikely. LIMITATIONS, REASONS FOR CAUTION: The main limitation of the study is the lack of experimental validation of the role of PPP1R12A in Müllerian regression. Only circumstantial evidence is available, myosin phosphatase is required for cell mobility, which plays a major role in Müllerian regression. Alternatively, PPP1R12A mutations could affect the AMH transduction pathway. WIDER IMPLICATIONS OF THE FINDINGS: The study supports the conclusion that failure of Müllerian regression in males is not necessarily associated with a defect in AMH signaling. Extending the scope of molecular analysis should shed light upon the mechanism of the initial steps of male sex differentiation. STUDY FUNDING/COMPETING INTEREST(S): The study was funded by la Fondation Maladies Rares, GenOmics 2021_0404 and la Fondation pour la Recherche Médicale, grant EQU201903007868. The authors report no conflict of interest. TRIAL REGISTRATION NUMBER: N/A.


Asunto(s)
Trastorno del Desarrollo Sexual 46,XY , Humanos , Masculino , Fosfatasa de Miosina de Cadena Ligera/genética , Trastorno del Desarrollo Sexual 46,XY/genética , Hormona Antimülleriana/genética , Hormona Antimülleriana/metabolismo , ADN
6.
Blood ; 131(14): 1545-1555, 2018 04 05.
Artículo en Inglés | MEDLINE | ID: mdl-29378696

RESUMEN

Previous data have suggested that B-cell-depletion therapy may induce the settlement of autoreactive long-lived plasma cells (LLPCs) in the spleen of patients with autoimmune cytopenia. To investigate this process, we used the AID-CreERT2-EYFP mouse model to follow plasma cells (PCs) engaged in an immune response. Multiplex polymerase chain reaction at the single-cell level revealed that only a small fraction of splenic PCs had a long-lived signature, whereas PCs present after anti-CD20 antibody treatment appeared more mature, similar to bone marrow PCs. This observation suggested that, in addition to a process of selection, a maturation induced on B-cell depletion drove PCs toward a long-lived program. We showed that B-cell activating factor (BAFF) and CD4+ T cells play a major role in the PC survival niche, because combining anti-CD20 with anti-BAFF or anti-CD4 antibody greatly reduce the number of splenic PCs. Similar results were obtained in the lupus-prone NZB/W model. These different contributions of soluble and cellular components of the PC niche in the spleen demonstrate that the LLPC expression profile is not cell intrinsic but largely depends on signals provided by the splenic microenvironment, implying that interfering with these components at the time of B-cell depletion might improve the response rate in autoimmune cytopenia.


Asunto(s)
Factor Activador de Células B/inmunología , Linfocitos T CD4-Positivos/inmunología , Lupus Eritematoso Sistémico/inmunología , Depleción Linfocítica , Células Plasmáticas/inmunología , Bazo/inmunología , Animales , Linfocitos T CD4-Positivos/patología , Supervivencia Celular , Modelos Animales de Enfermedad , Lupus Eritematoso Sistémico/patología , Ratones , Células Plasmáticas/patología , Bazo/patología
7.
Am J Hum Genet ; 98(5): 971-980, 2016 May 05.
Artículo en Inglés | MEDLINE | ID: mdl-27108797

RESUMEN

Gillespie syndrome (GS) is a rare variant form of aniridia characterized by non-progressive cerebellar ataxia, intellectual disability, and iris hypoplasia. Unlike the more common dominant and sporadic forms of aniridia, there has been no significant association with PAX6 mutations in individuals with GS and the mode of inheritance of the disease had long been regarded as uncertain. Using a combination of trio-based whole-exome sequencing and Sanger sequencing in five simplex GS-affected families, we found homozygous or compound heterozygous truncating mutations (c.4672C>T [p.Gln1558(∗)], c.2182C>T [p.Arg728(∗)], c.6366+3A>T [p.Gly2102Valfs5(∗)], and c.6664+5G>T [p.Ala2221Valfs23(∗)]) and de novo heterozygous mutations (c.7687_7689del [p.Lys2563del] and c.7659T>G [p.Phe2553Leu]) in the inositol 1,4,5-trisphosphate receptor type 1 gene (ITPR1). ITPR1 encodes one of the three members of the IP3-receptors family that form Ca(2+) release channels localized predominantly in membranes of endoplasmic reticulum Ca(2+) stores. The truncation mutants, which encompass the IP3-binding domain and varying lengths of the modulatory domain, did not form functional channels when produced in a heterologous cell system. Furthermore, ITPR1 p.Lys2563del mutant did not form IP3-induced Ca(2+) channels but exerted a negative effect when co-produced with wild-type ITPR1 channel activity. In total, these results demonstrate biallelic and monoallelic ITPR1 mutations as the underlying genetic defects for Gillespie syndrome, further extending the spectrum of ITPR1-related diseases.


Asunto(s)
Aniridia/etiología , Ataxia Cerebelosa/etiología , Genes Dominantes/genética , Genes Recesivos/genética , Receptores de Inositol 1,4,5-Trifosfato/genética , Discapacidad Intelectual/etiología , Mutación/genética , Adolescente , Aniridia/patología , Ataxia Cerebelosa/patología , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Discapacidad Intelectual/patología , Masculino , Linaje
8.
Am J Hum Genet ; 97(2): 311-8, 2015 Aug 06.
Artículo en Inglés | MEDLINE | ID: mdl-26166481

RESUMEN

KIAA0586, the human ortholog of chicken TALPID3, is a centrosomal protein that is essential for primary ciliogenesis. Its disruption in animal models causes defects attributed to abnormal hedgehog signaling; these defects include polydactyly and abnormal dorsoventral patterning of the neural tube. Here, we report homozygous mutations of KIAA0586 in four families affected by lethal ciliopathies ranging from a hydrolethalus phenotype to short-rib polydactyly. We show defective ciliogenesis, as well as abnormal response to SHH-signaling activation in cells derived from affected individuals, consistent with a role of KIAA0586 in primary cilia biogenesis. Whereas centriolar maturation seemed unaffected in mutant cells, we observed an abnormal extended pattern of CEP290, a centriolar satellite protein previously associated with ciliopathies. Our data show the crucial role of KIAA0586 in human primary ciliogenesis and subsequent abnormal hedgehog signaling through abnormal GLI3 processing. Our results thus establish that KIAA0586 mutations cause lethal ciliopathies.


Asunto(s)
Proteínas de Ciclo Celular/genética , Trastornos de la Motilidad Ciliar/genética , Codón sin Sentido/genética , Deformidades Congénitas de la Mano/genética , Cardiopatías Congénitas/genética , Hidrocefalia/genética , Fenotipo , Síndrome de Costilla Pequeña y Polidactilia/genética , Secuencia de Bases , Trastornos de la Motilidad Ciliar/patología , Europa Oriental , Resultado Fatal , Efecto Fundador , Humanos , Funciones de Verosimilitud , Datos de Secuencia Molecular , Linaje , Análisis de Secuencia de ADN
9.
Am J Med Genet A ; 176(5): 1091-1098, 2018 05.
Artículo en Inglés | MEDLINE | ID: mdl-29681083

RESUMEN

Corpus callosum (CC) is the major brain commissure connecting homologous areas of cerebral hemispheres. CC anomalies (CCAs) are the most frequent brain anomalies leading to variable neurodevelopmental outcomes making genetic counseling difficult in the absence of a known etiology that might inform the prognosis. Here, we used whole exome sequencing, and a targeted capture panel of syndromic CCA known causal and candidate genes to screen a cohort of 64 fetuses with CCA observed upon autopsy, and 34 children with CCA and intellectual disability. In one fetus and two patients, we identified three novel de novo mutations in ZBTB20, which was previously shown to be causal in Primrose syndrome. In addition to CCA, all cases presented with additional features of Primrose syndrome including facial dysmorphism and macrocephaly or megalencephaly. All three variations occurred within two out of the five zinc finger domains of the transcriptional repressor ZBTB20. Through homology modeling, these variants are predicted to result in local destabilization of each zinc finger domain suggesting subsequent abnormal repression of ZBTB20 target genes. Neurohistopathological analysis of the fetal case showed abnormal regionalization of the hippocampal formation as well as a reduced density of cortical upper layers where originate most callosal projections. Here, we report novel de novo ZBTB20 mutations in three independent cases with characteristic features of Primrose syndrome including constant CCA. Neurohistopathological findings in fetal case corroborate the observed key role of ZBTB20 during hippocampal and neocortical development. Finally, this study highlights the crucial role of ZBTB20 in CC development in human.


Asunto(s)
Anomalías Múltiples/diagnóstico , Anomalías Múltiples/genética , Agenesia del Cuerpo Calloso/diagnóstico , Agenesia del Cuerpo Calloso/genética , Calcinosis/diagnóstico , Calcinosis/genética , Enfermedades del Oído/diagnóstico , Enfermedades del Oído/genética , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/genética , Atrofia Muscular/diagnóstico , Atrofia Muscular/genética , Mutación , Proteínas del Tejido Nervioso/genética , Factores de Transcripción/genética , Adolescente , Secuencia de Aminoácidos , Encéfalo/anomalías , Encéfalo/diagnóstico por imagen , Niño , Femenino , Secuenciación de Nucleótidos de Alto Rendimiento , Humanos , Recién Nacido , Masculino , Proteínas del Tejido Nervioso/química , Conformación de Ácido Nucleico , Linaje , Fenotipo , Conformación Proteica , Reproducibilidad de los Resultados , Análisis de Secuencia de ADN , Factores de Transcripción/química
10.
Brain ; 140(10): 2597-2609, 2017 Oct 01.
Artículo en Inglés | MEDLINE | ID: mdl-28969387

RESUMEN

Microlissencephaly is a rare brain malformation characterized by congenital microcephaly and lissencephaly. Microlissencephaly is suspected to result from abnormalities in the proliferation or survival of neural progenitors. Despite the recent identification of six genes involved in microlissencephaly, the pathophysiological basis of this condition remains poorly understood. We performed trio-based whole exome sequencing in seven subjects from five non-consanguineous families who presented with either microcephaly or microlissencephaly. This led to the identification of compound heterozygous mutations in WDR81, a gene previously associated with cerebellar ataxia, intellectual disability and quadrupedal locomotion. Patient phenotypes ranged from severe microcephaly with extremely reduced gyration with pontocerebellar hypoplasia to moderate microcephaly with cerebellar atrophy. In patient fibroblast cells, WDR81 mutations were associated with increased mitotic index and delayed prometaphase/metaphase transition. Similarly, in vivo, we showed that knockdown of the WDR81 orthologue in Drosophila led to increased mitotic index of neural stem cells with delayed mitotic progression. In summary, we highlight the broad phenotypic spectrum of WDR81-related brain malformations, which include microcephaly with moderate to extremely reduced gyration and cerebellar anomalies. Our results suggest that WDR81 might have a role in mitosis that is conserved between Drosophila and humans.


Asunto(s)
Fibroblastos/citología , Microcefalia/genética , Microcefalia/patología , Mitosis/genética , Mutación/genética , Proteínas del Tejido Nervioso/genética , Células-Madre Neurales/citología , Animales , Animales Modificados Genéticamente , Encéfalo/diagnóstico por imagen , Encéfalo/patología , Células Cultivadas , Preescolar , Drosophila , Proteínas de Drosophila/genética , Proteínas de Drosophila/metabolismo , Femenino , Fibroblastos/patología , Regulación de la Expresión Génica/genética , Humanos , Antígeno Ki-67/metabolismo , Masculino , Microcefalia/diagnóstico por imagen , Células-Madre Neurales/patología , Interferencia de ARN/fisiología , Adulto Joven
11.
J Med Genet ; 54(5): 324-329, 2017 05.
Artículo en Inglés | MEDLINE | ID: mdl-28069933

RESUMEN

BACKGROUND: While mitochondrial DNA (mtDNA) copy number is strictly regulated during differentiation and according to cell type, very little is known regarding the mechanism which accurately controls mtDNA copy number in human. Exon 2 of the human POLG gene, encoding the catalytic subunit of the mitochondrial-specific DNA polymerase gamma, contains a CpG island, highly conserved in mice and human. Changes of DNA methylation at the POLG locus have been shown to modulate mtDNA copy number during cell differentiation in both mouse and human. METHODS: We have investigated the epigenetic modification of the POLG gene, by assessing the methylation level of its exon 2 using deep-Next Generation Sequencing analysis of bisulfite-treated DNA. Analysis were performed on various tissues at either postnatal or prenatal stages, on samples from carriers of mtDNA mutations, patients carrying two loss-of-function POLG mutations and controls. RESULTS: Very high methylation levels at POLG exon 2 were found (94±3%) and no variation was observed according to either developmental stage or tissue of origin, except for sperm samples for which lower methylation levels were found (80%). This high level of methylation was neither correlated with the presence of mtDNA mutations (94±1% of methylated alleles), nor with biallelic POLG mutations (93%±2%), even in tissues where a mtDNA depletion had been observed. CONCLUSIONS: This study suggests that, at variance with mouse and un/de-differentiated human cells, differentiated human cells control mtDNA levels irrespective of POLG methylation. The factors which actually control the mtDNA levels in such cell types remain to be identified.


Asunto(s)
Diferenciación Celular/genética , Islas de CpG/genética , Metilación de ADN/genética , ADN Polimerasa gamma/genética , ADN Mitocondrial/genética , Exones/genética , Mutación/genética , Adolescente , Adulto , Animales , Secuencia de Bases , Niño , Preescolar , Femenino , Humanos , Lactante , Recién Nacido , Ratones , Persona de Mediana Edad , Embarazo , Adulto Joven
12.
J Allergy Clin Immunol ; 147(2): 734-737, 2021 02.
Artículo en Inglés | MEDLINE | ID: mdl-32531373
13.
Am J Hum Genet ; 92(2): 265-70, 2013 Feb 07.
Artículo en Inglés | MEDLINE | ID: mdl-23312594

RESUMEN

Anophthalmia and microphthalmia (A/M) are early-eye-development anomalies resulting in absent or small ocular globes, respectively. A/M anomalies occur in syndromic or nonsyndromic forms. They are genetically heterogeneous, some mutations in some genes being responsible for both anophthalmia and microphthalmia. Using a combination of homozygosity mapping, exome sequencing, and Sanger sequencing, we identified homozygosity for one splice-site and two missense mutations in the gene encoding the A3 isoform of the aldehyde dehydrogenase 1 (ALDH1A3) in three consanguineous families segregating A/M with occasional orbital cystic, neurological, and cardiac anomalies. ALDH1A3 is a key enzyme in the formation of a retinoic acid gradient along the dorso-ventral axis during early eye development. Transitory expression of mutant ALDH1A3 open reading frames showed that both missense mutations reduce the accumulation of the enzyme, potentially leading to altered retinoic acid synthesis. Although the role of retinoic acid signaling in eye development is well established, our findings provide genetic evidence of a direct link between retinoic-acid-synthesis dysfunction and early-eye-development anomalies in humans.


Asunto(s)
Aldehído Deshidrogenasa/genética , Anoftalmos/enzimología , Anoftalmos/genética , Genes Recesivos/genética , Microftalmía/enzimología , Microftalmía/genética , Mutación/genética , Aldehído Oxidorreductasas , Segregación Cromosómica/genética , Exones/genética , Femenino , Ligamiento Genético , Células HEK293 , Homocigoto , Humanos , Intrones/genética , Masculino , Proteínas Mutantes/metabolismo , Linaje , Análisis de Secuencia de ADN
14.
Blood ; 122(23): 3713-22, 2013 Nov 28.
Artículo en Inglés | MEDLINE | ID: mdl-24089328

RESUMEN

Monogenic interleukin-10 (IL-10) and IL-10 receptor (IL-10R) deficiencies cause very early onset severe inflammatory bowel disease. Here, we report that 5 patients with an IL-10R1 (n = 1) or IL-10R2 (n = 4) deficiency developed B-cell non-Hodgkin lymphoma between the ages of 5 and 6 years (which was recurrent in 1 patient). These lymphomas had some of the characteristics of diffuse large B-cell lymphomas and contained monoclonal, Epstein-Barr virus-negative germinal center B cells. The tumors displayed a remarkably homogeneous signature, with original activation of the nuclear factor κB pathway and a decrease in intratumor T-cell infiltration. Hence, IL-10R deficiency is associated with a high risk of developing B-cell lymphoma. Our results revealed an unexpected role of the IL-10R pathway in lymphomagenesis.


Asunto(s)
Subunidad alfa del Receptor de Interleucina-10/deficiencia , Subunidad alfa del Receptor de Interleucina-10/genética , Subunidad beta del Receptor de Interleucina-10/deficiencia , Subunidad beta del Receptor de Interleucina-10/genética , Linfoma de Células B/genética , Linfoma de Células B/inmunología , Adolescente , Edad de Inicio , Niño , Preescolar , Femenino , Perfilación de la Expresión Génica , Genes rel , Predisposición Genética a la Enfermedad , Centro Germinal/inmunología , Centro Germinal/patología , Humanos , Enfermedades Inflamatorias del Intestino/complicaciones , Enfermedades Inflamatorias del Intestino/genética , Enfermedades Inflamatorias del Intestino/inmunología , Interleucina-10/metabolismo , Linfoma de Células B/etiología , Linfoma de Células B Grandes Difuso/etiología , Linfoma de Células B Grandes Difuso/genética , Linfoma de Células B Grandes Difuso/inmunología , Masculino , Mutación , FN-kappa B/metabolismo , Linaje , Transducción de Señal
15.
Am J Med Genet A ; 167A(8): 1908-12, 2015 Aug.
Artículo en Inglés | MEDLINE | ID: mdl-25846674

RESUMEN

Intellectual disability is a neurodevelopmental disorder of impaired adaptive skills and low intelligence quotient. The overall prevalence is estimated at 2-3% in the general population with extreme clinical and genetic heterogeneity, and it has been associated with possibly causative mutations in more than 700 identified genes. In a recent review, among over 100 X-linked intellectual disability causative genes, eight were reported as "awaiting replication." Exome sequencing in a large family identified a missense mutation in RPL10 highly suggestive of X-linked intellectual disability. Herein, we report on the clinical description of four affected males. All patients presented apparent intellectual disability (4/4), psychomotor delay (4/4) with syndromic features including amniotic fluid excess (3/4), microcephaly (2/4), urogenital anomalies (3/4), cerebellar syndrome (2/4), and facial dysmorphism. In the literature, two mutations were reported in three families with affected males presenting with autism. This report confirms the implication of RPL10 mutations in neurodevelopmental disorders and extends the associated clinical spectrum from autism to syndromic intellectual disability.


Asunto(s)
Enfermedades Genéticas Ligadas al Cromosoma X/genética , Discapacidad Intelectual/genética , Proteínas Ribosómicas/genética , Femenino , Humanos , Masculino , Linaje , Proteína Ribosómica L10
16.
Sci Adv ; 10(25): eadl2468, 2024 Jun 21.
Artículo en Inglés | MEDLINE | ID: mdl-38896620

RESUMEN

The third millennium BCE was a pivotal period of profound cultural and genomic transformations in Europe associated with migrations from the Pontic-Caspian steppe, which shaped the ancestry patterns in the present-day European genome. We performed a high-resolution whole-genome analysis including haplotype phasing of seven individuals of a collective burial from ~2500 cal BCE and of a Bell Beaker individual from ~2300 cal BCE in the Paris Basin in France. The collective burial revealed the arrival in real time of steppe ancestry in France. We reconstructed the genome of an unsampled individual through its relatives' genomes, enabling us to shed light on the early-stage admixture patterns, dynamics, and propagation of steppe ancestry in Late Neolithic Europe. We identified two major Neolithic/steppe-related ancestry admixture pulses around 3000/2900 BCE and 2600 BCE. These pulses suggest different population expansion dynamics with striking links to the Corded Ware and Bell Beaker cultural complexes.


Asunto(s)
Entierro , Genoma Humano , Haplotipos , Humanos , Entierro/historia , Población Blanca/genética , Genética de Población , Historia Antigua , Migración Humana , Europa (Continente) , ADN Antiguo/análisis , Dinámica Poblacional , Francia
17.
Acta Neuropathol Commun ; 11(1): 29, 2023 02 20.
Artículo en Inglés | MEDLINE | ID: mdl-36803301

RESUMEN

Congenital hydrocephalus is a common condition caused by the accumulation of cerebrospinal fluid in the ventricular system. Four major genes are currently known to be causally involved in hydrocephalus, either isolated or as a common clinical feature: L1CAM, AP1S2, MPDZ and CCDC88C. Here, we report 3 cases from 2 families with congenital hydrocephalus due to bi-allelic variations in CRB2, a gene previously reported to cause nephrotic syndrome, variably associated with hydrocephalus. While 2 cases presented with renal cysts, one case presented with isolated hydrocephalus. Neurohistopathological analysis allowed us to demonstrate that, contrary to what was previously proposed, the pathological mechanisms underlying hydrocephalus secondary to CRB2 variations are not due to stenosis but to atresia of both Sylvius Aqueduct and central medullar canal. While CRB2 has been largely shown crucial for apico-basal polarity, immunolabelling experiments in our fetal cases showed normal localization and level of PAR complex components (PKCι and PKCζ) as well as of tight (ZO-1) and adherens (ß-catenin and N-Cadherin) junction molecules indicating a priori normal apicobasal polarity and cell-cell adhesion of the ventricular epithelium suggesting another pathological mechanism. Interestingly, atresia but not stenosis of Sylvius aqueduct was also described in cases with variations in MPDZ and CCDC88C encoding proteins previously linked functionally to the Crumbs (CRB) polarity complex, and all 3 being more recently involved in apical constriction, a process crucial for the formation of the central medullar canal. Overall, our findings argue for a common mechanism of CRB2, MPDZ and CCDC88C variations that might lead to abnormal apical constriction of the ventricular cells of the neural tube that will form the ependymal cells lining the definitive central canal of the medulla. Our study thus highlights that hydrocephalus related to CRB2, MPDZ and CCDC88C constitutes a separate pathogenic group of congenital non-communicating hydrocephalus with atresia of both Sylvius aqueduct and central canal of the medulla.


Asunto(s)
Acueducto del Mesencéfalo , Hidrocefalia , Humanos , Acueducto del Mesencéfalo/patología , Polaridad Celular/genética , Hidrocefalia/patología , Proteínas , Proteínas Portadoras/genética , Proteínas de la Membrana/genética , Proteínas de Microfilamentos , Péptidos y Proteínas de Señalización Intracelular
18.
Birth Defects Res ; 114(10): 499-504, 2022 06.
Artículo en Inglés | MEDLINE | ID: mdl-35426486

RESUMEN

BACKGROUND: The THOC6 protein is a component of the THO complex. It is involved in mRNA transcription, processing and nuclear export. Interestingly molecular biallelic loss-of-function variants of the THOC6 gene were identified in the Beaulieu-Boycott-Innes syndrome (BBIS- OMIM # 613680). This condition was described in 17 patients and is characterized by a moderate to severe intellectual disability, facial dysmorphic features and severe birth defects such as heart, skeletal, ano-genital and renal congenital malformations. METHODS: In the present study, we report on a new family with two affected sibs. The 6-year-old female had severe intellectual disability with autistic features, feeding difficulties, growth delay, facial dysmorphic, and congenital malformations (hand, skeletal and cardiac anomalies). The male fetus presented antenatally with a cystic hygroma associated with severe aortic and left ventricular hypoplasia. Autopsy, after termination of pregnancy at 15 weeks of gestation, showed facial dysmorphic, short right thumb and hypospadias. RESULTS: Exome sequencing detected in both sibs compound heterozygous variants of the THOC6 gene (NM_024339.3, GRCh37): the already reported c.[298T>A;700G>T;824G>A] haplotype and a novel variant c.977T>G, p.(Val326Gly). DISCUSSION: We made a review of the literature of 17 BBIS reported patients including our two siblings. Severe to moderate ID and congenital malformations were constant. Prenatal and postnatal failure to thrive were frequent. Brain MRI were not specific. Prenatal findings were reported in 40% of cases but we described the first case of cystic hygroma. The present study reports extends the prenatal delineation of the phenotypic features observed in association with the presence of THOC6 variants. In addition, it underscores the intrafamilial phenotypic variability observed in BBIS.


Asunto(s)
Discapacidad Intelectual , Linfangioma Quístico , Microcefalia , Anomalías Musculoesqueléticas , Proteínas de Unión al ARN , Femenino , Humanos , Discapacidad Intelectual/genética , Masculino , Anomalías Musculoesqueléticas/genética , Fenotipo , Embarazo , Proteínas de Unión al ARN/genética , Secuenciación del Exoma
19.
Eur J Hum Genet ; 30(8): 960-966, 2022 08.
Artículo en Inglés | MEDLINE | ID: mdl-35590056

RESUMEN

DNA polymerase δ is one of the three main enzymes responsible for DNA replication. POLD1 heterozygous missense variants in the exonuclease domain result in a cancer predisposition phenotype. In contrast, heterozygous variants in POLD1 polymerase domain have more recently been shown to be the underlying basis of the distinct autosomal dominant multisystem lipodystrophy disorder, MDPL (mandibular hypoplasia, deafness, progeroid features, and lipodystrophy syndrome OMIM # 615381), most commonly a recurrent in-frame deletion of serine at position 604, accounting for 18 of the 21 reported cases of this condition. One patient with an unusually severe phenotype has been reported, caused by a de novo c. 3209 T > A, (p.(Ile1070Asn)) variant in the highly conserved CysB motif in the C-terminal of the POLD1 protein. This region has recently been shown to bind an iron-sulphur cluster of the 4Fe-4S type. This report concerns a novel de novo missense variant in the CysB region, c.3219 G > C, (p.(Ser1073Arg)) in a male child with a milder phenotype. Using in silico analysis in the context of the recently published structure of human Polymerase δ holoenzyme, we compared these and other variants which lie in close proximity but result in differing degrees of severity and varying features. We hypothesise that the c.3219 G > C, (p.(Ser1073Arg)) substitution likely causes reduced binding of the iron-sulphur cluster without significant disruption of protein structure, while the previously reported c.3209 T > A (p.(Ile1070Asn)) variant likely has a more profound impact on structure and folding in the region. Our analysis supports a central role for the CysB region in regulating POLD1 activity in health and disease.


Asunto(s)
ADN Polimerasa III , Proteínas Hierro-Azufre , Lipodistrofia , Niño , ADN Polimerasa III/genética , Humanos , Proteínas Hierro-Azufre/genética , Lipodistrofia/genética , Masculino , Mutación Missense , Fenotipo , Síndrome
20.
J Clin Invest ; 131(3)2021 02 01.
Artículo en Inglés | MEDLINE | ID: mdl-33290277

RESUMEN

Inborn errors of immunity cause monogenic immune dysregulatory conditions such as severe and recurrent pathogen infection, inflammation, allergy, and malignancy. Somatic reversion refers to the spontaneous repair of a pathogenic germline genetic variant and has been reported to occur in a number of inborn errors of immunity, with a range of impacts on clinical outcomes of these conditions. DOCK8 deficiency due to biallelic inactivating mutations in DOCK8 causes a combined immunodeficiency characterized by severe bacterial, viral, and fungal infections, as well as allergic disease and some cancers. Here, we describe the clinical, genetic, and cellular features of 3 patients with biallelic DOCK8 variants who, following somatic reversion in multiple lymphocyte subsets, exhibited improved clinical features, including complete resolution of infection and allergic disease, and cure over time. Acquisition of DOCK8 expression restored defective lymphocyte signalling, survival and proliferation, as well as CD8+ T cell cytotoxicity, CD4+ T cell cytokine production, and memory B cell generation compared with typical DOCK8-deficient patients. Our temporal analysis of DOCK8-revertant and DOCK8-deficient cells within the same individual established mechanisms of clinical improvement in these patients following somatic reversion and revealed further nonredundant functions of DOCK8 in human lymphocyte biology. Last, our findings have significant implications for future therapeutic options for the treatment of DOCK8 deficiency.


Asunto(s)
Diferenciación Celular , Factores de Intercambio de Guanina Nucleótido/deficiencia , Memoria Inmunológica/genética , Activación de Linfocitos/genética , Linfocitos/inmunología , Inmunodeficiencia Combinada Grave , Adulto , Diferenciación Celular/genética , Diferenciación Celular/inmunología , Femenino , Humanos , Masculino , Inmunodeficiencia Combinada Grave/genética , Inmunodeficiencia Combinada Grave/inmunología
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