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1.
Am J Med Genet A ; 194(4): e63481, 2024 Apr.
Artículo en Inglés | MEDLINE | ID: mdl-37984424

RESUMEN

Chanarin-Dorfman syndrome is an autosomal recessively inherited disorder characterized by ichthyosis, sensorineural hearing loss, and hepatic dysfunction. We report on a 60-year-old female of Venezuelan descent who presented with congenital ichthyosis, progressive sensorineural hearing loss, and liver cirrhosis. We identify a heterozygous copy number deletion involving exon 1 and another heterozygous deletion involving exon 3 of the ABHD5 gene. Exon 2 is preserved. Both deletions were confirmed with RT-PCR. RNAseq from peripheral blood shows a reduction of ABHD5 expression overall and an absence of exon 3 expression, confirming the deleterious effects of the identified deletions. We present exonic deletions as a potentially common type of ABHD5 variation.


Asunto(s)
Pérdida Auditiva Sensorineural , Eritrodermia Ictiosiforme Congénita , Ictiosis , Errores Innatos del Metabolismo Lipídico , Enfermedades Musculares , Femenino , Humanos , Persona de Mediana Edad , Eritrodermia Ictiosiforme Congénita/complicaciones , Eritrodermia Ictiosiforme Congénita/diagnóstico , Eritrodermia Ictiosiforme Congénita/genética , Errores Innatos del Metabolismo Lipídico/genética , Enfermedades Musculares/genética , Ictiosis/complicaciones , Ictiosis/diagnóstico , Ictiosis/genética , Cirrosis Hepática , Pérdida Auditiva Sensorineural/complicaciones , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/genética , 1-Acilglicerol-3-Fosfato O-Aciltransferasa/genética
2.
Am J Med Genet A ; 185(1): 208-212, 2021 01.
Artículo en Inglés | MEDLINE | ID: mdl-33037780

RESUMEN

We report the first case of blood chimerism involving a pathogenic RB1 variant in naturally conceived monochorionic-dizygotic twins (MC/DZ) with the twin-twin-transfusion syndrome (TTTS), presumably caused by the exchange of stem-cells. Twin A developed bilateral retinoblastoma at 7 months of age. Initial genetic testing identified a de novo RB1 pathogenic variant, with a 20% allelic ratio in both twins' blood. Subsequent genotyping of blood and skin confirmed dizygosity, with the affected twin harboring the RB1 pathogenic variant in skin and blood, and the unaffected twin carrying the variant only in blood.


Asunto(s)
Transfusión Feto-Fetal/sangre , Proteína de Retinoblastoma/genética , Retinoblastoma/sangre , Gemelos Dicigóticos/genética , Quimerismo , Femenino , Transfusión Feto-Fetal/genética , Transfusión Feto-Fetal/patología , Humanos , Lactante , Embarazo , Embarazo Gemelar/sangre , Embarazo Gemelar/genética , Retinoblastoma/genética , Retinoblastoma/patología , Proteína de Retinoblastoma/sangre , Células Madre/metabolismo , Células Madre/patología , Gemelos Monocigóticos/genética , Ultrasonografía Prenatal
3.
Am J Med Genet A ; 185(11): 3446-3458, 2021 11.
Artículo en Inglés | MEDLINE | ID: mdl-34436830

RESUMEN

The study aimed at widening the clinical and genetic spectrum of ASXL3-related syndrome, a neurodevelopmental disorder, caused by truncating variants in the ASXL3 gene. In this international collaborative study, we have undertaken a detailed clinical and molecular analysis of 45 previously unpublished individuals with ASXL3-related syndrome, as well as a review of all previously published individuals. We have reviewed the rather limited functional characterization of pathogenic variants in ASXL3 and discuss current understanding of the consequences of the different ASXL3 variants. In this comprehensive analysis of ASXL3-related syndrome, we define its natural history and clinical evolution occurring with age. We report familial ASXL3 pathogenic variants, characterize the phenotype in mildly affected individuals and discuss nonpenetrance. We also discuss the role of missense variants in ASXL3. We delineate a variable but consistent phenotype. The most characteristic features are neurodevelopmental delay with consistently limited speech, significant neuro-behavioral issues, hypotonia, and feeding difficulties. Distinctive features include downslanting palpebral fissures, hypertelorism, tubular nose with a prominent nasal bridge, and low-hanging columella. The presented data will inform clinical management of individuals with ASXL3-related syndrome and improve interpretation of new ASXL3 sequence variants.


Asunto(s)
Discapacidades del Desarrollo/genética , Predisposición Genética a la Enfermedad , Trastornos del Neurodesarrollo/genética , Factores de Transcripción/genética , Adolescente , Adulto , Niño , Preescolar , Discapacidades del Desarrollo/epidemiología , Discapacidades del Desarrollo/fisiopatología , Femenino , Variación Genética/genética , Humanos , Hipertelorismo/genética , Hipertelorismo/fisiopatología , Discapacidad Intelectual/genética , Discapacidad Intelectual/fisiopatología , Masculino , Hipotonía Muscular/genética , Hipotonía Muscular/fisiopatología , Mutación/genética , Trastornos del Neurodesarrollo/epidemiología , Trastornos del Neurodesarrollo/fisiopatología , Fenotipo , Adulto Joven
4.
Am J Med Genet A ; 182(3): 548-552, 2020 03.
Artículo en Inglés | MEDLINE | ID: mdl-31833199

RESUMEN

ZMIZ1, zinc finger MIZ-domain containing 1, has recently been described in association with syndromic intellectual disability in which the primary phenotypic features include intellectual disability/developmental delay, seizures, hearing loss, behavioral issues, failure to thrive, and various congenital malformations. Most reported cases have been found to result from de novo mutations except for one set of three siblings in which parental testing could not be performed. With informed consent from the family, we report on a father and his two sons demonstrating autosomal dominant inheritance of a novel pathogenic ZMIZ1 variant, c.1310delC (p.Pro437ArgfsX84), causing this recently described neurodevelopmental syndrome. While they all show syndromic findings along with short stature and intellectual disability, only one child had sensorineural hearing loss. Moreover, severity of intellectual disability and eyelid ptosis were variable among the affected members. Our report demonstrates that phenotypic features of ZMIZ1-related neurodevelopmental syndrome are variable even within the same family and that parental testing to identify a mildly affected parent is needed.


Asunto(s)
Pérdida Auditiva Sensorineural/genética , Discapacidad Intelectual/genética , Malformaciones del Sistema Nervioso/genética , Trastornos del Neurodesarrollo/genética , Factores de Transcripción/genética , Anciano , Alelos , Niño , Preescolar , Exoma/genética , Femenino , Predisposición Genética a la Enfermedad , Pérdida Auditiva Sensorineural/complicaciones , Pérdida Auditiva Sensorineural/diagnóstico , Pérdida Auditiva Sensorineural/patología , Humanos , Discapacidad Intelectual/complicaciones , Discapacidad Intelectual/diagnóstico , Discapacidad Intelectual/patología , Masculino , Persona de Mediana Edad , Mutación/genética , Malformaciones del Sistema Nervioso/diagnóstico , Malformaciones del Sistema Nervioso/patología , Trastornos del Neurodesarrollo/complicaciones , Trastornos del Neurodesarrollo/diagnóstico , Trastornos del Neurodesarrollo/patología , Padres , Hermanos
5.
ACS Chem Biol ; 9(6): 1359-68, 2014 Jun 20.
Artículo en Inglés | MEDLINE | ID: mdl-24742366

RESUMEN

Phosphoinositides are low abundance membrane phospholipids that have key roles in signaling, membrane trafficking, and cytoskeletal dynamics in all cells. Until recently, strategies for robust and quantitative development of pharmacological tools for manipulating phosphoinositide levels have focused selectively on PI(3,4,5)P3 due to the importance of this lipid in growth factor signaling and cell proliferation. However, drugs that affect levels of other phosphoinositides have potential therapeutic applications and will be powerful research tools. Here, we describe methodology for the high-throughput screening of small molecule modulators of the inositol 5-phosphatases, which dephosphorylate PI(4,5)P2 (the precursor for PI(3,4,5)P3) and PI(3,4,5)P3). We developed three complementary in vitro activity assays, tested hit compounds on a panel of 5-phosphatases, and monitored efficacy toward various substrates. Two prominent chemical scaffolds were identified with high nanomolar/low micromolar activity, with one class showing inhibitory activity toward all 5-phosphatases tested and the other selective activity toward OCRL and INPP5B, which are closely related to each other. One highly soluble OCRL/INPP5B-specific inhibitor shows a direct interaction with the catalytic domain of INPP5B. The efficacy of this compound in living cells was validated through its property to enhance actin nucleation at the cell cortex, a PI(4,5)P2 dependent process, and to inhibit PI(4,5)P2 dephosphorylation by OCRL (both overexpressed and endogenous enzyme). The assays and screening strategies described here are applicable to other phosphoinositide-metabolizing enzymes, at least several of which have major clinical relevance. Most importantly, this study identifies the first OCRL/INPP5B specific inhibitor and provides a platform for the design of more potent inhibitors of this family of enzymes.


Asunto(s)
Dermis/efectos de los fármacos , Inhibidores Enzimáticos/farmacología , Fibroblastos/efectos de los fármacos , Fosfatos de Fosfatidilinositol/metabolismo , Monoéster Fosfórico Hidrolasas/antagonistas & inhibidores , Bibliotecas de Moléculas Pequeñas/farmacología , Tiadiazoles/farmacología , Triazoles/farmacología , Células Cultivadas , Dermis/citología , Dermis/enzimología , Ensayo de Cambio de Movilidad Electroforética , Inhibidores Enzimáticos/química , Fibroblastos/citología , Fibroblastos/enzimología , Polarización de Fluorescencia , Ensayos Analíticos de Alto Rendimiento , Humanos , Inositol Polifosfato 5-Fosfatasas , Estructura Molecular , Monoéster Fosfórico Hidrolasas/genética , Monoéster Fosfórico Hidrolasas/metabolismo , Colorantes de Rosanilina , Transducción de Señal/efectos de los fármacos , Bibliotecas de Moléculas Pequeñas/química , Tiadiazoles/química , Triazoles/química
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