Hemoglobin McKees Rocks (alpha2beta2145Tyr leads to Term). A human "nonsense" mutation leading to a shortened beta-chain.

Winslow, Robert M.; Swenberg, M.-L.; Groß, Eva; Chervenick, Paul A.; Buchman, Robert R.; Anderson, W.F.

doi:10.1172/jci108336

Cited by 62 publications

(18 citation statements)

References 33 publications

(12 reference statements)

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“…Only three had signs and symptoms related to thrombosis (one each with However, only two cases of this hemoglobin variant have been reported to date. 13,25 To the best of our knowledge, this is the third case of hemoglobin McKees Rocks to be reported in the world literature, and the first from India. Another patient had a heterozygous HBB:c.437A > G mutation resulting in the formation of Hb Rainier.…”

Section: Congenital Erythrocytosis Patients Present At Varying Agesmentioning

confidence: 73%

Genetic basis of unexplained erythrocytosis in Indian patients

Mallik

Sharma

Hira

et al. 2019

European J of Haematology

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Objective To evaluate the spectrum of genetic defects in Indian patients with unexplained erythrocytosis. Methods Fifteen families (18 patients) with unexplained erythrocytosis were enrolled after excluding polycythemia vera and secondary erythrocytosis. Focused Sanger sequencing from genomic DNA was performed for EPOR (exon 8), VHL (exons 2‐3), EGLN1 (exons 2‐5), EPAS1 (exon 12), and all exons of HBB, HBA1, and HBA2 genes. Results Eleven of the 18 patients (including two pairs of brothers) had Chuvash polycythemia, that is, homozygosity for VHL:c.598C > T (p.Arg200Trp). Three patients (two of whom were brothers) had HBB mutations associated with increased oxygen‐affinity hemoglobin—one had a heterozygous Hb McKees Rocks HBB:c.438T > A (p.Tyr146*), and two brothers showed heterozygous Hb Rainier HBB:c.437A > G (p.Tyr146Cys). No pathogenic variants were found in the remaining four cases. Conclusion A gene‐by‐gene Sanger sequencing approach could determine a genetic basis for erythrocytosis in 11 of the 15 (73%) Indian families, with homozygous VHL:c.598C > T (p.Arg200Trp) being the commonest pathogenic variant. This first study from the Indian subcontinent provides a rationale for analyzing this variant in patients with suspected congenital erythrocytosis from this region. Rare first occurrences of Hb McKees Rocks and Hb Rainier in Indians are also being reported.

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Section: Congenital Erythrocytosis Patients Present At Varying Agesmentioning

confidence: 73%

Genetic basis of unexplained erythrocytosis in Indian patients

Mallik

Sharma

Hira

et al. 2019

European J of Haematology

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“…The a-116 mRNA accumulates in normal amounts. This is not unexpected since a /3-globin mRNA with a nonsense mutation at codon 145 (the normal length of / globin is 146 amino acids) makes normal levels of /3-globin protein (27) and, presumably, normal levels of /3-globin mRNA.…”

Section: Discussionmentioning

confidence: 94%

Nonsense mutations in the human beta-globin gene affect mRNA metabolism.

Baserga

Benz

1988

Proc. Natl. Acad. Sci. U.S.A.

202

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A number of premature translation termination mutations (nonsense mutations) have been described in the human a-and (8-globin genes. Studies on mRNA isolated from patients with IP-thalassemia have shown that for both the (3-17 and the (8-39 mutations less than normal levels of (8-globin mRNA accumulate in peripheral blood cells. (The codon at which the mutation occurs designates the name of the mutation; there are 146 codons in human (3-globin mRNA.) In vitro studies using the cloned (1-39 gene have reproduced this effect in a heterologous transfection system and have suggested that the defect resides in intranuclear metabolism. We have asked if this phenomenon of decreased mRNA accumulation is a general property of nonsense mutations and if the effect depends on the location or the type of mutation. Toward this end, we have studied the effect of five nonsense mutations and two missense mutations on the expression of human (3-globin mRNA in a heterologous transfection system. In all cases studied, the presence of a translation termination codon correlates with a decrease in the steady-state level of mRNA. The data suggest that the metabolism of a mammalian mRNA is affected by the presence of a mutation that affects translation.Many of the steps in /-globin gene expression have been well-studied. Globin mRNA is transcribed from DNA, spliced, polyadenylylated, and then translated into protein in the cytoplasm. Less is known about the determinants of nuclear and cytoplasmic globin mRNA stability and about nuclear-cytoplasmic transport. The /3-39 gene causes thalassemia because it encodes a truncated nonfunctional globin protein chain. (The codon at which the mutation occurs designates the name of the mutation.) Although the nonsense mutation at codon 39 affects translation, studies from our laboratory and others suggest that this mutation has an additional unexpected effect on mRNA metabolism (1-8).

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“…The penultimate Tyr at 145(HC2)8 is firmly held in the pocket made by the F and H helices in deoxyhemoglobin (Perutz, 1970). The natural mutants which have the mutation at the 1456 site such as Hb Osler (Tyr-1450 -Asp) and Hb McKees Rocks (Tyr-1450terminated) fail to retain a "T state" conformation in the deoxygenated form, resulting in a high oxygen affinity and low cooperativity (Charache et al, 1975;Winslow et al, 1976). Then, the tyrosine pocket becomes narrower and the Tyr side chain is expelled to cause the rupture of its hydrogen bond with Val-98(FG5)0 (Perutz, 1970;Baldwin & Chothia, 1979).…”

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confidence: 99%

Site-directed mutagenesis in hemoglobin: functional and structural role of inter- and intrasubunit hydrogen bonds as studied with 37.beta. and 145.beta. mutations

Ishimori

Imai²,

Miyazaki³

et al. 1992

Biochemistry

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In order to clarify the functional and structural role of intra- and intersubunit hydrogen bonds in human hemoglobin (Hb A), we prepared two artificial beta chain mutant hemoglobins by site-directed mutagenesis. The mutant Hb Phe-37 beta, in which Trp-37 beta is replaced by Phe to remove the intersubunit hydrogen bond between Asp-94 alpha and Trp-37 beta at the alpha 1-beta 2 interface in deoxy Hb A, showed a markedly increased oxygen affinity and almost completely diminished Bohr effect and cooperativity. However, 1H-NMR data indicated that the structure of deoxy Hb Phe-37 beta is rather similar to that of deoxy Hb A. The enhanced tetramer-to-dimer dissociation previously observed in Hb Hirose (Trp-37 beta----Ser) together with our observation of the effects of organic phosphate on the structure and function of Hb Phe-37 beta suggested that a large part of the abnormal properties of Hb Phe-37 beta observed for dilute solutions appears to result from partial dissociation into alpha beta dimers rather than direct destabilization of the T-quaternary structure in the deoxygenated state. Thus, the primary and direct role of the hydrogen bond between Asp-94 alpha and Trp-37 beta is to stabilize the tetrameric assembly, and thereby this hydrogen bond indirectly contributes to stabilization of the T-quaternary structure. The other mutant Hb Phe-145 beta has a Phe residue at the 145 beta site and lacks the intrasubunit hydrogen bond formed between Tyr-145 beta and the carbonyl group of Val-98 beta in deoxy Hb A.(ABSTRACT TRUNCATED AT 250 WORDS)

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Hemoglobin McKees Rocks (alpha2beta2145Tyr leads to Term). A human "nonsense" mutation leading to a shortened beta-chain.

Cited by 62 publications

References 33 publications

Genetic basis of unexplained erythrocytosis in Indian patients

Genetic basis of unexplained erythrocytosis in Indian patients

Nonsense mutations in the human beta-globin gene affect mRNA metabolism.

Site-directed mutagenesis in hemoglobin: functional and structural role of inter- and intrasubunit hydrogen bonds as studied with 37.beta. and 145.beta. mutations

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