RESUMEN
Ubiquitin ligases play an important role in the regulation of the immune system. Absence of Itch E3 ubiquitin ligase in mice has been shown to cause severe autoimmune disease. Using autozygosity mapping in a large Amish kindred, we identified a linkage region on chromosome 20 and selected candidate genes for screening. We describe, in ten patients, identification of a mutation resulting in truncation of ITCH. These patients represent the first reported human phenotype associated with ITCH deficiency. These patients not only have multisystem autoimmune disease but also display morphologic and developmental abnormalities. This disorder underscores the importance of ITCH ubiquitin ligase in many cellular processes.
Asunto(s)
Enfermedades Autoinmunes/enzimología , Enfermedades Autoinmunes/genética , Mutación del Sistema de Lectura , Proteínas Represoras/deficiencia , Proteínas Represoras/genética , Ubiquitina-Proteína Ligasas/deficiencia , Ubiquitina-Proteína Ligasas/genética , Secuencia de Aminoácidos , Enfermedades Autoinmunes/patología , Secuencia de Bases , Niño , Preescolar , Mapeo Cromosómico , Cromosomas Humanos Par 20/genética , Consanguinidad , ADN/genética , Discapacidades del Desarrollo/enzimología , Discapacidades del Desarrollo/genética , Etnicidad/genética , Femenino , Homocigoto , Humanos , Lactante , Masculino , Datos de Secuencia Molecular , Mutagénesis Insercional , Linaje , Fenotipo , Síndrome , Estados Unidos , Adulto JovenRESUMEN
PURPOSE: Mutations in the CDKL5 gene have been associated with an X-linked dominant early infantile epileptic encephalopathy-2. The clinical presentation is usually of severe encephalopathy with refractory seizures and Rett syndrome (RTT)-like phenotype. We attempted to assess the role of mosaic intragenic copy number variation in CDKL5. METHODS: We have used comparative genomic hybridization with a custom-designed clinical oligonucleotide array targeting exons of selected disease and candidate genes, including CDKL5. RESULTS: We have identified mosaic exonic deletions of CDKL5 in one male and two females with developmental delay and medically intractable seizures. These three mosaic changes represent 60% of all deletions detected in 12,000 patients analyzed by array comparative genomic hybridization and involving the exonic portion of CDKL5. CONCLUSION: We report the first case of an exonic deletion of CDKL5 in a male and emphasize the importance of underappreciated mosaic exonic copy number variation in patients with early-onset seizures and RTT-like features of both genders.
Asunto(s)
Exones/genética , Mosaicismo , Proteínas Serina-Treonina Quinasas/genética , Convulsiones/genética , Eliminación de Secuencia/genética , Edad de Inicio , Niño , Preescolar , Cromosomas Humanos X/genética , Femenino , Orden Génico , Humanos , Lactante , MasculinoRESUMEN
Seizures in neonates or young infants present a frequent diagnostic challenge. After exclusion of acquired causes, disturbances of the internal homeostasis and brain malformations, the physician must evaluate for inborn errors of metabolism and for other non-malformative genetic disorders as the cause of seizures. The metabolic causes can be categorized into disorders of neurotransmitter metabolism, disorders of energy production, and synthetic or catabolic disorders associated with brain malformation, dysfunction and degeneration. Other genetic conditions involve channelopathies, and disorders resulting in abnormal growth, differentiation and formation of neuronal populations. These conditions are important given their potential for treatment and the risk for recurrence in the family. In this paper, we will succinctly review the metabolic and genetic non-malformative causes of seizures in neonates and infants less than 6 months of age. We will then provide differential diagnostic clues and a practical paradigm for their evaluation.
Asunto(s)
Encéfalo/fisiopatología , Canalopatías/genética , Metabolismo Energético/fisiología , Neurogénesis/genética , Neurotransmisores/metabolismo , Convulsiones/diagnóstico , Convulsiones/etiología , Canalopatías/complicaciones , Diagnóstico Diferencial , Humanos , Lactante , Recién Nacido , Convulsiones/genética , Convulsiones/metabolismoRESUMEN
BACKGROUND: Syndromic hearing loss that results from contiguous gene deletions is uncommon. Deafness-infertility syndrome (DIS) is caused by large contiguous gene deletions at 15q15.3. METHODS: Three families with a novel syndrome characterised by deafness and infertility are described. These three families do not share a common ancestor and do not share identical deletions. Linkage was established by completing a genome-wide scan and candidate genes in the linked region were screened by direct sequencing. RESULTS: The deleted region is about 100 kb long and involves four genes (KIAA0377, CKMT1B, STRC and CATSPER2), each of which has a telomeric duplicate. This genomic architecture underlies the mechanism by which these deletions occur. CATSPER2 and STRC are expressed in the sperm and inner ear, respectively, consistent with the phenotype in persons homozygous for this deletion. A deletion of this region has been reported in one other family segregating male infertility and sensorineural deafness, although congenital dyserythropoietic anaemia type I (CDAI) was also present, presumably due to a second deletion in another genomic region. CONCLUSION: We have identified three families segregating an autosomal recessive contiguous gene deletion syndrome characterised by deafness and sperm dysmotility. This new syndrome is caused by the deletion of contiguous genes at 15q15.3.