RESUMEN
A previously unreported ß chain hemoglobin (Hb) variant, Hb Grove City [ß38(C4)ThrâSer, ACC>AGC; HBB: c.116C>G], was discovered in a woman who presented with hypoxia and mild anemia. Her young daughter also tested positive for the variant and displayed similar symptoms. Hemoglobin-oxygen dissociation testing confirmed right-shifted oxygen dissociation curves. A corresponding Hb variant was detected by high performance liquid chromatography (HPLC) and intact mass spectrometry (MS) but was not detected by capillary electrophoresis (CE), isoelectrofocusing (IEF) or alkaline or acid electrophoresis. DNA sequencing analysis confirmed a ß-globin gene mutation. All three previous mutations at this locus affect oxygen affinity, as does this new variant. This newly described variant showed variable stability results and therefore may be mildly unstable but is not associated with microcytosis, significant hemolysis or clinically evident cyanosis. It is important to consider hemoglobinopathies in patients who are anemic and have unexplained hypoxia. Arterial blood gas and p50 evaluations may prevent unnecessary diagnostic interventions. Additionally, Hb variants with altered oxygen affinity can be electrophoretically silent; therefore, multiple methods including MS and/or DNA sequencing are warranted when clinical suspicion is high.
Asunto(s)
Hemoglobinas Anormales/genética , Hemoglobinas Anormales/metabolismo , Mutación , Oxígeno/sangre , Globinas beta/genética , Globinas beta/metabolismo , Adulto , Secuencia de Bases , Análisis de los Gases de la Sangre , Preescolar , Cromatografía Líquida de Alta Presión , Femenino , Hemoglobinopatías/sangre , Hemoglobinopatías/diagnóstico , Hemoglobinopatías/genética , Hemoglobinas Anormales/química , Humanos , Hipoxia , Espectrometría de Masas , Análisis de Secuencia de ADN , Globinas beta/químicaRESUMEN
A new high oxygen affinity hemoglobin (Hb) variant, Hb Nebraska [ß86(F2)AlaâIle, GCC>ATC; HGVS: HBB: c.259G>A;260C>T] is reported. This variant was not identified by routine methods and was only suspected due to erythrocytosis and an abnormal p50 value. The variant was analyzed by DNA sequencing and mass spectrometry (MS). The ß chain variant is unusual in that it has two nucleotide substitutions occurring at the same codon.
Asunto(s)
Sustitución de Aminoácidos , Globinas/genética , Hemoglobinas Anormales/genética , Hemoglobinas Anormales/metabolismo , Oxígeno/metabolismo , Alanina/genética , Secuencia de Bases , Codón , Femenino , Humanos , Isoleucina/genética , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Nebraska , Nucleótidos , Policitemia/genéticaRESUMEN
A new ß hemoglobin (Hb) variant, Hb Cambridge-MA [ß144(HC1)ß146(HC3)Lys-Tyr-Hisâ0 (AAG>TAG) (HGVS: HBB c.433 A>T] is described. The variant was characterized by high performance liquid chromatography (HPLC), alkaline, acid, globin chain and capillary electrophoresis, isoelectric focusing (IEF), heat and isopropanol stability, p50 analyses, intact globin mass spectrometry (MS) and DNA sequencing. The new variant shows high oxygen (O2) affinity and is associated with mild polycythemia.
Asunto(s)
Hemoglobinas Anormales/genética , Globinas beta/genética , Secuencia de Bases , Cromatografía Líquida de Alta Presión , Análisis Mutacional de ADN , Electroforesis Capilar , Femenino , Hemoglobinas Anormales/metabolismo , Humanos , Focalización Isoeléctrica , Espectrometría de Masas , Persona de Mediana Edad , Oxígeno/metabolismo , Mutación Puntual , Policitemia/genética , Policitemia/patología , Globinas beta/metabolismoRESUMEN
The influence of germ line BRCA2 unclassified variants (UCV), including missense mutations and in-frame deletions and insertions on BRCA2 function and on cancer risk, has not been defined although these mutations account for 43% of all identified BRCA2 sequence alterations. To investigate the effects of UCVs on BRCA2 function, we compared mutant and wild-type forms of BRCA2 using assays of cellular survival and viability, homologous recombination repair, and genome instability. We confirm that the effects of known deleterious mutations can be distinguished from neutral polymorphisms and wild-type BRCA2 in these assays, and we characterize the influence of a series of UCVs on BRCA2 function. We also describe how the results from the assays can be combined with data from analysis of cosegregation of the UCVs with cancer, co-occurrence of the UCVs with other deleterious mutations, and interspecies sequence variation in a comprehensive framework in an effort to better distinguish between disease predisposing and neutral UCVs. This combined approach represents a useful means of addressing the functional significance and cancer relevance of UCVs in BRCA2.
Asunto(s)
Genes BRCA2/fisiología , Mutación , Neoplasias/genética , Animales , Proteína BRCA2/biosíntesis , Proteína BRCA2/genética , Proteína BRCA2/metabolismo , Proteína BRCA2/fisiología , Centrosoma/fisiología , Segregación Cromosómica , Reactivos de Enlaces Cruzados/efectos adversos , ADN Complementario/genética , Hipersensibilidad a las Drogas/genética , Amplificación de Genes , Predisposición Genética a la Enfermedad , Humanos , Mitomicina/efectos adversos , Mutagénesis Sitio-Dirigida , Alineación de Secuencia , TransfecciónRESUMEN
OBJECTIVES: Soluble ST2 (ST2) and galectin-3 (Gal3) are biomarkers of myocardial fibrosis and remodeling. This study provides a foundation for the use of ST2 and Gal3 in pediatric patients by assessing values of these biomarkers among children without heart failure. DESIGN AND METHODS: Sera from 240 children, 40 males and 40 females from each of three age groups, (2-6 years, 7-11 years, and 12-17 years) without heart failure were identified from residual clinical testing. Serum ST2 and Gal3 were measured by ELISA. RESULTS: Serum ST2 increased with age among males, but not females. However, the difference was not statistically significant at the 95th or 97.5th percentiles. No relationship was found between serum Gal3 concentrations and age or gender. Central 95th percentiles (2.5th to 97.5th) were 9-50 ng/mL for ST2 and 7-33 ng/mL for Gal3. CONCLUSIONS: We have presented baseline, normative data for ST2 and Gal3 in children. This will allow for study of the utility of these biomarkers in children with heart disease.