ABSTRACT
We describe a case with a low oxygen affinity hemoglobin (Hb) variant who presented with cyanosis in the absence of cardiopulmonary disease. The patient, a 27-year-old pregnant female (P1G2), complained of a productive cough and bluish discoloration of the lips that started 3 days prior to seeking attention. She had no previous episodes and has generally been in good health. A positive family history of cyanosis was obtained in one sibling. Systematic examination, notably the cardiorespiratory system, revealed no abnormalities. The arterial Hb oxygen saturation (SpO2) on pulse oximetry was 81.0% and Hb separation studies revealed an Hb variant identified as Hb Rothschild [ß37(C3)TrpâArg] (HBB: c.[112 T>A or 112 T>C]) by gene sequencing. The amino acid substitution (TrpâArg) is an important contact point at the α1ß2 interface and favors a T-quaternary state of the Hb tetramer. This leads to a low oxygen affinity state, which results in premature release of oxygen and drop in oxygen saturation. In the absence of cardiopulmonary disease, a decreased oxygen saturation reading, with or without cyanosis, should arouse suspicion for a possible dysHb.
Subject(s)
Erythrocyte Indices , Hemoglobins, Abnormal , Oximetry , Pregnancy Complications, Hematologic , Adult , Cyanosis/blood , Cyanosis/genetics , Female , Hemoglobins, Abnormal/genetics , Hemoglobins, Abnormal/metabolism , Humans , Pregnancy , Pregnancy Complications, Hematologic/blood , Pregnancy Complications, Hematologic/geneticsABSTRACT
Elucidating genetic causes of cholestasis has proved to be important in understanding the physiology and pathophysiology of the liver. Here we show that protein-truncating mutations in the tight junction protein 2 gene (TJP2) cause failure of protein localization and disruption of tight-junction structure, leading to severe cholestatic liver disease. These findings contrast with those in the embryonic-lethal knockout mouse, highlighting differences in redundancy in junctional complexes between organs and species.
Subject(s)
Cholestasis, Intrahepatic/genetics , Mutation/genetics , Tight Junctions/pathology , Zonula Occludens-2 Protein/genetics , Animals , Base Sequence , Cholestasis, Intrahepatic/physiopathology , High-Throughput Nucleotide Sequencing , Humans , Immunoblotting , Immunohistochemistry , Mice , Mice, Knockout , Microscopy, Electron, Transmission , Models, Biological , Molecular Sequence Data , Pedigree , Real-Time Polymerase Chain Reaction , Sequence Alignment , Species Specificity , Tight Junctions/geneticsABSTRACT
Mutations within the promoters of either of the γ-globin genes [(G)γ (HBG1) and (A)γ (HBG2)] lead to variably increased levels of fetal hemoglobin (Hb) (Hb F, α2γ2) in the syndrome of hereditary persistence of fetal Hb (HPFH). Carriers of such mutations are clinically asymptomatic and the mutations are usually detected as part of routine screening or family studies. We describe two new nondeletional HPFH mutations, both C > T substitutions at position c.-250, one in the HBG1 and the other in the HBG2 globin gene promoters.
