RESUMEN
Cullin 4B (CUL4B), lysosomal-associated membrane protein Type 2 (LAMP2), ATP1B4, TMEM255A, and ZBTB33 are neighboring genes on Xq24. Mutations in CUL4B result in Cabezas syndrome (CS). Male CS patients present with dysmorphic, neuropsychiatric, genitourinary, and endocrine abnormalities. Heterozygous CS females are clinically asymptomatic. LAMP2 mutations cause Danon disease (DD). Cardiomyopathy is a dominant feature of DD present in both males and heterozygous females. No monogenic phenotypes have been associated with mutations in ATP1B4, TMEM255A, and ZBTB33 genes. To facilitate diagnostics and counseling in CS and DD families, we present a female DD patient with a de novo Alu-mediated Xq24 rearrangement causing a deletion encompassing CUL4B, LAMP2, and also the other three neighboring genes. Typical to females heterozygous for CUL4B mutations, the patient was CS asymptomatic, however, presented with extremely skewed X-chromosome inactivation (XCI) ratios in peripheral white blood cells. As a result of the likely selection against CUL4B deficient clones, only minimal populations (~3%) of LAMP2 deficient leukocytes were identified by flow cytometry. On the contrary, myocardial LAMP2 protein expression suggested random XCI. We demonstrate that contiguous CUL4B and LAMP2 loss-of-function copy number variations occur and speculate that male patients carrying similar defects could present with features of both CS and DD.
Asunto(s)
Proteínas Cullin/genética , Enfermedad por Depósito de Glucógeno de Tipo IIb/genética , Proteína 2 de la Membrana Asociada a los Lisosomas/genética , Discapacidad Intelectual Ligada al Cromosoma X/genética , Adulto , Elementos Alu/genética , Cardiomiopatías/genética , Cardiomiopatías/fisiopatología , Deleción Cromosómica , Variaciones en el Número de Copia de ADN/genética , Exones/genética , Femenino , Enfermedad por Depósito de Glucógeno de Tipo IIb/diagnóstico , Enfermedad por Depósito de Glucógeno de Tipo IIb/fisiopatología , Humanos , Mutación con Pérdida de Función/genética , Masculino , Discapacidad Intelectual Ligada al Cromosoma X/fisiopatología , Miocardio/metabolismo , ATPasa Intercambiadora de Sodio-Potasio/genética , Factores de Transcripción/genética , Inactivación del Cromosoma X/genéticaRESUMEN
Heterochromatin variants are commonly found during cytogenetic examinations, and chromosomes 1, 9, 16 and Y are commonly involved in these variations. These variants are believed to be clinically insignificant variations in human karyotypes. Nevertheless, reproductive failure has been frequently discussed as possibly being associated with these variants. Various authors have reported a significantly elevated incidence of these variants in individuals with idiopathic reproductive failure compared with individuals with no such history. This study compared the incidence of heterochromatin variants in individuals with idiopathic reproductive failure (n=1036) with that of a control group of healthy fetuses (n=995) indicated for prenatal karyotype examination solely based on the advanced ages of their mothers. The heterochromatin variants occurred more frequently in the reproductive failure group than in the controls (P=0.006). Regarding individual chromosomes, chromosome 9 variants were most frequently found in the study and control groups, and they also occurred more frequently in the reproductive failure group. The most significant difference between the study and control groups was found for the 9qh+ variant (P=0.026), and although the results are statistically significant, the cause of this phenomenon remains unknown.
Asunto(s)
Heterocromatina/genética , Infertilidad Femenina/genética , Infertilidad Masculina/genética , Cariotipificación , Femenino , Humanos , Masculino , Estudios RetrospectivosRESUMEN
UNLABELLED: We established and characterized a new IL-6 dependent multiple myeloma (MM) cell line UHKT-893 from the bone marrow of a relapsed 57-year-old woman. RESULTS: Using nephelometry, cells with plasma cell phenotype and morphology were found to secrete IgG and free kappa (κ)-light chain of immunoglobulin. κ-Light chain was also recognized intracellularly by flow cytometry and by mass spectrometry. VH4-39 region of IgVH genes was rearranged and somatically hypermutated. Cytogenetic analysis of cells revealed new chromosome abnormalities in all breakpoints unique in both MM patients and cell lines - t(1;6), t(1;11), t(5;15), t(5;21), +der(11;15) and der(16). IL-6 independent subline UHKT-893a was established by adaptation to descending IL-6 concentration, while the original cell line keeps on maintaining its IL-6 dependency. CONCLUSION: The cell line provides a suitable material for cellular and molecular studies of tumor abnormalities, with potentially unique mutagenic features of myeloma disease. It may be utilized for human hybridoma construction and vaccine development. Both IL-6 dependent and independent cell clones represent an important model for studies of myeloma cell growth and resistance emerging during targeted therapy.
Asunto(s)
Mieloma Múltiple/patología , Cultivo Primario de Células , Células de la Médula Ósea/efectos de los fármacos , Células de la Médula Ósea/patología , Células de la Médula Ósea/fisiología , Línea Celular Tumoral , Proliferación Celular/efectos de los fármacos , Análisis Citogenético , Femenino , Humanos , Interleucina-6/farmacología , Persona de Mediana Edad , Cultivo Primario de Células/métodos , RecurrenciaRESUMEN
AIMS: The aim of our study was to scan for cryptic rearrangements using the multiplex ligation probe amplification method in a cohort of 64 probands with mental retardation or developmental delays in combination with at least one of the following symptoms: hypotonia after birth, congenital anomalies, or face dysmorphisms; but without a positive cytogenetic finding. The study contributes to the knowledge of microdeletion syndromes and helps disclose their natural phenotypic variability. RESULTS: In total, 10 positives (16%) were detected, particularly 3 duplications (Xpter-p22.32; 17p11.2; 22q11) and 6 different deletions (1p36; 7q11.23; 10p15; 15q11-q13; 17p11.2; 17p13.3), 1 of these in 2 probands. Besides the well-characterized syndromes, less-often described rearrangements with ambiguous phenotype associations were also detected. CONCLUSIONS: Some rearrangements, particularly duplications, are associated with vague phenotypes; and their frequency could be underestimated.