Red cell adenylate kinase deficiency: molecular study of 3 new mutations (118G&amp;gt;A, 190G&amp;gt;A, and GAC deletion) associated with hereditary nonspherocytic hemolytic anemia

Corrons, Joan‐Lluís Vives; García, Elena Fernández; Tusell, Joan J.; Varughese, Kottayil I.; West, Carol; Beutler, Ernest

doi:10.1182/blood-2002-07-2288

Cited by 12 publications

(11 citation statements)

References 13 publications

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“…In this report, we have investigated molecular defect of AK deficiency in a 6-year-old male child from Indian origin born of a nonconsanguineous marriage. In our case, the clinical presentation was very similar with the previously reported cases without mental and psychomotor retardation 14. The psychomotor impairment is generally associated with AK deficiency, although the mechanisms responsible are not well understood.…”

Section: Discussionsupporting

confidence: 88%

Red cell adenylate kinase deficiency in India: identification of two novel missense mutations (c.71A>G and c.413G>A)

Dongerdiye

Kamat²,

Jain³

et al. 2019

J Clin Pathol

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Adenylate kinase (AK) deficiency is a rare erythroenzymopathy associated with hereditary nonspherocytic haemolytic anaemia along with mental/psychomotor retardation in few cases. Diagnosis of AK deficiency depends on the decreased level of enzyme activity in red cell and identification of a mutation in the AK1 gene. Until, only eight mutations causing AK deficiency have been reported in the literature. We are reporting two novel missense mutation (c.71A > G and c.413G > A) detected in the AK1 gene by next-generation sequencing (NGS) in a 6-year-old male child from India. Red cell AK enzyme activity was found to be 30% normal. We have screened a total of 32 family members of the patient and showed reduced red cell enzyme activity and confirm mutations by Sanger’s sequencing. On the basis of Sanger sequencing, we suggest that the proband has inherited a mutation in AK1 gene exon 4 c.71A > G (p.Gln24Arg) from paternal family and exon 6 c.413G > A (p.Arg138His) from maternal family. Bioinformatics tools, such as SIFT, Polymorphism Phenotyping v.2, Mutation Taster, MutPred, also confirmed the deleterious effect of both the mutations. Molecular modelling suggests that the structural changes induced by p.Gln24Arg and p.Arg138His are pathogenic variants having a direct impact on the structural arrangement of the region close to the active site of the enzyme. In conclusion, NGS will be the best solution for diagnosis of very rare disorders leading to better management of the disease. This is the first report of the red cell AK deficiency from the Indian population.

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Section: Discussionsupporting

confidence: 88%

Red cell adenylate kinase deficiency in India: identification of two novel missense mutations (c.71A>G and c.413G>A)

Dongerdiye

Kamat²,

Jain³

et al. 2019

J Clin Pathol

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“…This enzyme coordinates different signaling pathways, ensuring adequate response to a broad range of functional, environmental and stress stimuli. In such a way, AK plays a key role in the cell and its dysfunction is connected to the onset of several human diseases, such as heart failure, metabolic disorders, cancer and neurodegenerative diseases 1 2 .…”

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confidence: 99%

Energetics and Structural Characterization of the large-scale Functional Motion of Adenylate Kinase

Formoso

Limongelli

Parrinello

2015

Sci Rep

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Adenylate Kinase (AK) is a signal transducing protein that regulates cellular energy homeostasis balancing between different conformations. An alteration of its activity can lead to severe pathologies such as heart failure, cancer and neurodegenerative diseases. A comprehensive elucidation of the large-scale conformational motions that rule the functional mechanism of this enzyme is of great value to guide rationally the development of new medications. Here using a metadynamics-based computational protocol we elucidate the thermodynamics and structural properties underlying the AK functional transitions. The free energy estimation of the conformational motions of the enzyme allows characterizing the sequence of events that regulate its action. We reveal the atomistic details of the most relevant enzyme states, identifying residues such as Arg119 and Lys13, which play a key role during the conformational transitions and represent druggable spots to design enzyme inhibitors. Our study offers tools that open new areas of investigation on large-scale motion in proteins.

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“…Now as days, conventional Sanger sequencing, is generally used in a routine diagnostic tool for many genetic disorders but has its limitation in identifying de novo mutations whereas the variant is very rare and that is located outside of the captured regions, NGS targeted panel is very useful for identifying rare blood disorder. NGS has a higher diagnostic value as it has high accuracy and rapidly adapted in the genetic analysis [9]. Therefore, we used a targeted NGS panel for the analysis of 100 genes responsible for rare congenital anaemias, which successfully helped in identifying novel mutations in the AK1 gene in Indian patients.…”

Section: Discussionmentioning

confidence: 99%

“…The panel mainly includes targeted genes that are associated with red cell haemolglobinopathies, enzymopathies, red cell membrane disorders, congenital dyserythropoietic anaemias, and bone marrow failure syndromes. These NGS gene panels covered a sequence of coding regions, splice site junctions, and deep intronic regions, and regulatory regions, which has the advantages to overcome all the problems in the diagnosis of unexplained haemolytic anaemia cases, especially in identifying de novo mutations [9]. This NGS panel gives fast and accurate results for identifying the genetic diagnosis in patients with unexplained congenital haemolytic anaemia.…”

Section: Introductionmentioning

confidence: 99%

Rare hereditary nonspherocytic hemolytic anemia caused by novel homozygous mutation, c.301C>A, (Q101K) in the AK1 gene in an Indian family

Dongerdiye

Sampagar²,

Devendra

et al. 2021

Preprint

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BackgroundAdenylate kinase (AK) deficiency is an uncommon form of congenital non-spherocytic haemolytic anaemia. To date, only 13 families have been affected by this disorder exhibiting symptoms like chronic anaemia supported by recurrent blood transfusions, jaundice, hepatosplenomegaly, and mental and psychomotor retardation in exceptional cases. This study aimed to identify a pathogenic mutation in the undiagnosed case of haemolytic anemia and to offer a parental diagnosis in the subsequent pregnancy.MethodNext-generation sequencing (NGS) was performed to identify pathogenic variants in the patient. Prenatal diagnosis during the second pregnancy was performed on genetic testing was performed on chronic villus sample (CVS) collected in 11 weeks of pregnancy from the mother and intravenous blood was drawn from both the parents.ResultsNovel causative mutation (p. Gln101Lys) in the AK gene was identified in a 5-year-old male child with severe transfusion-dependent hemolytic anemia. Bioinformatics tools predicted the deleterious effect of the novel variant on the structure of the protein. Prenatal diagnosis of the fetus was found to be heterozygous for the mutation. Both the parents were heterozygous for the variant c.301C > A, p. Gln101Lys.ConclusionWe have presented a review of the literature and novel mutations in the AK1 gene (p. Gln101Lys) associated with adenylate kinase deficiency. It is first a prenatal diagnosis AK deficiency report from India where heterogeneity is too high in the population and custom of intra-community marriages are prevalent.

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Red cell adenylate kinase deficiency: molecular study of 3 new mutations (118G>A, 190G>A, and GAC deletion) associated with hereditary nonspherocytic hemolytic anemia

Cited by 12 publications

References 13 publications

Red cell adenylate kinase deficiency in India: identification of two novel missense mutations (c.71A>G and c.413G>A)

Red cell adenylate kinase deficiency in India: identification of two novel missense mutations (c.71A>G and c.413G>A)

Energetics and Structural Characterization of the large-scale Functional Motion of Adenylate Kinase

Rare hereditary nonspherocytic hemolytic anemia caused by novel homozygous mutation, c.301C>A, (Q101K) in the AK1 gene in an Indian family

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Red cell adenylate kinase deficiency: molecular study of 3 new mutations (118G&gt;A, 190G&gt;A, and GAC deletion) associated with hereditary nonspherocytic hemolytic anemia

Cited by 12 publications

References 13 publications

Red cell adenylate kinase deficiency in India: identification of two novel missense mutations (c.71A>G and c.413G>A)

Red cell adenylate kinase deficiency in India: identification of two novel missense mutations (c.71A>G and c.413G>A)

Energetics and Structural Characterization of the large-scale Functional Motion of Adenylate Kinase

Rare hereditary nonspherocytic hemolytic anemia caused by novel homozygous mutation, c.301C&gt;A, (Q101K) in the AK1 gene in an Indian family

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Resources

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Red cell adenylate kinase deficiency: molecular study of 3 new mutations (118G>A, 190G>A, and GAC deletion) associated with hereditary nonspherocytic hemolytic anemia

Rare hereditary nonspherocytic hemolytic anemia caused by novel homozygous mutation, c.301C>A, (Q101K) in the AK1 gene in an Indian family