Transgenic rescue of hemolytic anemia due to red blood cell pyruvate kinase deficiency

Kanno, Hitoshi; Utsugisawa, Taiju; Aizawa, Shin; Koizumi, Tsutomu; Aisaki, Ken‐ichi; Hamada, Takako; Ogura, Hiromi; Fujii, H.

doi:10.3324/haematol.10945

Cited by 15 publications

(11 citation statements)

References 26 publications

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“…Sample preparation for OPT was essentially as described [43] and images were acquired using standard methods [44], [45]. Micro-CT samples were immersed in iodine [46] to generate soft tissue contrast and imaging was performed as previously published [47], [48].…”

Section: Methodsmentioning

confidence: 99%

ENU-induced Mutation in the DNA-binding Domain of KLF3 Reveals Important Roles for KLF3 in Cardiovascular Development and Function in Mice

Kelsey

Flenniken

et al. 2013

PLoS Genet

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KLF3 is a Krüppel family zinc finger transcription factor with widespread tissue expression and no previously known role in heart development. In a screen for dominant mutations affecting cardiovascular function in N-ethyl-N-nitrosourea (ENU) mutagenized mice, we identified a missense mutation in the Klf3 gene that caused aortic valvular stenosis and partially penetrant perinatal lethality in heterozygotes. All homozygotes died as embryos. In the first of three zinc fingers, a point mutation changed a highly conserved histidine at amino acid 275 to arginine (Klf3H275R). This change impaired binding of the mutant protein to KLF3's canonical DNA binding sequence. Heterozygous Klf3H275R mutants that died as neonates had marked biventricular cardiac hypertrophy with diminished cardiac chambers. Adult survivors exhibited hypotension, cardiac hypertrophy with enlarged cardiac chambers, and aortic valvular stenosis. A dominant negative effect on protein function was inferred by the similarity in phenotype between heterozygous Klf3H275R mutants and homozygous Klf3 null mice. However, the existence of divergent traits suggested the involvement of additional interactions. We conclude that KLF3 plays diverse and important roles in cardiovascular development and function in mice, and that amino acid 275 is critical for normal KLF3 protein function. Future exploration of the KLF3 pathway provides a new avenue for investigating causative factors contributing to cardiovascular disorders in humans.

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Section: Methodsmentioning

confidence: 99%

ENU-induced Mutation in the DNA-binding Domain of KLF3 Reveals Important Roles for KLF3 in Cardiovascular Development and Function in Mice

Kelsey

Flenniken

et al. 2013

PLoS Genet

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“…Studies in mice have shown prolonged expression of PK in the blood and hematopoietic organs of mice after introduction of a viral vector expressing human liver‐type PK cDNA . In addition, other investigators have shown increased expression of PK in transgenic mice using a gene‐addition strategy, although this did not fully rescue the mice from their phenotype with continued evidence of ineffective erythropoiesis .…”

Section: Future Directions For Therapymentioning

confidence: 99%

Erythrocyte pyruvate kinase deficiency: 2015 status report

et al. 2015

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Over the last several decades, our understanding of the genetic variation, pathophysiology, and complications of the hemolytic anemia associated with red cell pyruvate kinase deficiency (PKD) has expanded. Nonetheless, there remain significant gaps in our knowledge with regard to clinical care and monitoring. Treatment remains supportive with phototherapy and/or exchange transfusion in the newborn period, regular or intermittent red cell transfusions in children and adults, and splenectomy to decrease transfusion requirements and/or anemia related symptoms. In this article, we review the clinical diversity of PKD, the current standard of treatment and for supportive care, the complications observed, and future treatment directions.Am. J. Hematol. 90:825–830, 2015. © 2015 Wiley Periodicals, Inc.

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“…20 Gene transfer is currently being studied as an alternative approach, and successful gene transfer of the PKLR gene into human cell lines and mouse models has occurred. 21,22 Future studies are needed to determine if gene transfer will be a successful therapy for patients with PKD.…”

Section: Discussionmentioning

confidence: 99%

Anemia in the Neonate: The Differential Diagnosis and Treatment

Nassin¹,

Lapping-Carr²,

Jong³

2015

Pediatr Ann

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Anemia is a common problem in the neonatal period. Presenting symptoms may suggest numerous possible diagnoses ranging from anemia seen as a normal part of development to anemia due to critical pathology. An illustrative case is presented to highlight the appropriate evaluation of the neonate with significant anemia. Several important features of the evaluation of neonatal anemia are highlighted. The constellation of signs and symptoms that occur in conjunction with the anemia are critical for the evaluation. The evaluation should be performed in a step-wise process that starts by eliminating common causes of anemia. Manual review of the peripheral blood smear with a hematologist can be helpful.

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Transgenic rescue of hemolytic anemia due to red blood cell pyruvate kinase deficiency

Cited by 15 publications

References 26 publications

ENU-induced Mutation in the DNA-binding Domain of KLF3 Reveals Important Roles for KLF3 in Cardiovascular Development and Function in Mice

ENU-induced Mutation in the DNA-binding Domain of KLF3 Reveals Important Roles for KLF3 in Cardiovascular Development and Function in Mice

Erythrocyte pyruvate kinase deficiency: 2015 status report

Anemia in the Neonate: The Differential Diagnosis and Treatment

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