The Biologic Implications of a Rare Hemoglobin Mutant That Decreases Oxygen Affinity

Abstract

Blood from seven newborns, a 13-y-old, and seven adult family members with a suspected hemoglobinopathy because of unexplained cyanosis was obtained for analysis to determine Hb oxygen affinity and to characterize and quantify the Hb variants. Their oxygen saturation was 76 to 84%. The P 50 was 30.3 Ϯ 2.9 for the newborns and 32.5 Ϯ 2.6 mm Hg for their related adults. In the same order, the plasma erythropoietin was 7.4 Ϯ 2.9 and 15.9 Ϯ 3.7 mU/mL, whereas 2,3-diphosphoglycerate was 16.1. Ϯ 2.9 and 15.9 Ϯ 3.7 mol/g Hb. In four of the newborns with increased P 50 , the mother had a normal P 50 (27 mm Hg), which indicated a greater maternal oxygen affinity than the fetus with no adverse effects on the fetus. Genetic analysis of ␣-globin genes demonstrated a heterozygous mutation on the ␣2 gene [␣94(G1)Asp3 His] for each of the newborns and their related adults. The same mutation was found on the ␣1 gene in an adolescent and her father. The mRNA measurements showed that the ␣2-to ␣1-globin mRNA mean ratio was 2.5, ␣2 mutant globin mRNA/total ␣2-globin mRNA was 45.0%, whereas the ␣1 mutant globin mRNA/total ␣1-globin mRNA was 37.8%. The level of ␣2 mutant globin/total ␣-globin was 27.3 Ϯ 1%, and ␣1 mutant globin/total ␣-globin was 23.8 Ϯ 1%. The percentage of synthesized ␣2 and ␣1 mutant globins was 27.5 Ϯ 2 and 26.1 Ϯ 1, respectively. The ratio of the ␣2/␣1 mutant globins was 1.1, which corresponded to a ratio at the mRNA level of ␣2/␣1 of 2.5 Ϯ 0.5, which suggested that there is a less efficient translation of the ␣2 mRNA than ␣1 mRNA. The reversal of the physiologic fetomaternal oxygen affinity had no effects on fetal development. Abbreviations ODC, Hb-oxygen dissociation curve DPG, 2,3-diphosphoglycerate P 50 , PO 2 required to achieve a saturation of 50% at pH 7.4 and 37°CA rare mutant Hb with a low oxygen affinity designated as Sunshine Seth [␣94(G 1 ) Asp3 His] (1) was detected in a series of newborn infants as well as in a 13-y-old and her father. The infants, because of persistent cyanosis, were transferred soon after birth to a neonatal intensive care unit to investigate the cause of their Hb desaturation. The cyanotic infants and their parents provided an opportunity to evaluate the physiologic implications of low oxygen Hb affinity during the perinatal period as well as carry out genetic analysis to further the knowledge of the of human ␣-globin gene expression.The two human ␣-globin genes ␣1 and ␣2 are coexpressed in normal erythroid cells and encode identical ␣-globin protein products. The ␣2 gene encodes a 2-3-fold higher level of mRNA than the ␣1 gene (2). Because of the identical ␣-globin produced, the relative levels of expression are difficult to determine. Despite some data that suggest posttranscriptional/ translational modifications balancing the amount of protein expressed from these mRNA (3), it is still controversial how the difference in ␣2 and ␣1 mRNA levels are reflected at the protein level (4). Because of a rare occasion in which an identical mutation in both the ␣1 and ␣2 genes existed ...

Unexpectedly low pulse oximetry measurements associated with variant hemoglobins: A systematic review

“…We excluded 357 articles after screening titles and abstracts by using our predefined inclusion and exclusion criteria. Supplemental review of references, and consultation with content experts yielded an additional nine publications for review [6–14]. Forty‐eight publications were retrieved for detailed evaluation, of which 23 were excluded for the following reasons: not a case report ( n = 5); SpO 2 not reported ( n = 5); normal O 2 saturation by SpO 2 ( n = 1); severe respiratory illness during evaluation ( n = 1); and methemoglobinemia without documented congenital Hb M variant ( n = 11).…”

Hemoglobin Sunshine Seth: A Case Report of Low-Oxygen-Affinity Hemoglobinopathy

“…DNA sequencing confirmed a heterozygous GAC > CAC, Asp > His missense mutation at codon 94 in the α-globin gene (Human Genome Variation Society nomenclature, HBA2 c.283 G > C, p.D95H), resulting in Hb Sunshine Seth, an α-globin variant with low oxygen affinity. e Hb variant percentage was slightly lower than expected (15.9%; reference range, 26.3%-28.3%) [18]; however, the patient had concomitant iron deficiency (ferritin, 16 mcg/L; reference range, 24-336 mcg/L), which may have decreased the variant percentage. His parents were not tested for the genetic mutation.…”

“…It has been sequenced only 11 times in more than 20 years at our institution, and an additional 10 to 15 cases have been reported in the literature [22][23][24]. All reported infants appeared normal or slightly cyanotic at birth, and pulse oximetry showed low peripheral oxygen saturation (range, 76%-84%) [18]. e genetic mutation has been detected with cord blood screening, maternal screening, or evaluation of known familial cases.…”

Erratum to: Unexpectedly low pulse oximetry measurements associated with variant hemoglobins: A systematic review

“…There are four other variant hemoglobins (Hbs Sunshine Seth [9], Louisville [14], Chico [27], and Nishinomiya [46]) and three methemoglobins (Hbs M‐Milwaukee [47], F‐Circleville [11] and FM‐Fort Ripley [8]) all of which have decreased SpO 2 , with unreported or uncertain SaO 2 (Supporting Information—Table III).…”