Clinical Chemistry 47: 1967-1973, 2001;
(Clinical Chemistry. 2001;47:1967-1973.)
© 2001 American Association for Clinical Chemistry, Inc.
Creatine Kinase Gene Mutation in a Patient with Muscle Creatine Kinase Deficiency
Hiroshi Yamamichi1,
Shinpei Kasakura1,
Shunzi Yamamori2,
Ryu Iwasaki2,
Takumi Jikimoto3,
Sugayo Kanagawa3,
Jiro Ohkawa4,
Shunichi Kumagai3 and
Masahiro Koshiba3a
1
Department of Clinical Pathology, Kobe City General Hospital, 4-6 Minatojima-Nakamachi, Chuo-ku, Kobe 650-0046, Japan.
2
Department of Gene Analysis, Mitsubishi Kagaku Bio-Clinical Laboratories, Inc., 3-30-1, Shimura, Itabashi-Ku, Tokyo 175-0081, Japan.
3
Department of Clinical and Laboratory Medicine, Kobe University School of Medicine, 7-5-1 Kusunoki-cho, Chuo-ku, Kobe 650-0017, Japan.
4
Department of Pathology, Hyogo Medical Center for Adults, 13-70 Kitaoji, Akashi, Hyogo 673-0021, Japan.
aAuthor for correspondence. Fax 81-78-382-6209; e-mail mkoshiba{at}med kobe-u.ac.jp
 |
Abstract
|
|---|
Background: We describe a 56-year-old woman admitted to the hospital with a diagnosis of acute myocardial infarction without an increase of serum creatine kinase (CK) activity during her clinical course. She died on the 11th hospital day, and the diagnosis was confirmed by autopsy. The patient had had no previous muscular symptoms.
Methods: Expression of the CK-muscle (CK-M) protein in cardiac tissue was examined by immunoblotting and immunochemical staining. CK-M mRNA expression was estimated by semiquantitative reverse transcription–PCR. Gene structure of CK-M was determined by Southern blotting and direct sequencing of 2251 bp. Existence of a point mutation in the CK-M gene was examined by restriction fragment length polymorphism analysis of PCR products (PCR-RFLP) in the patient and in 108 controls.
Results: CK-M protein in the myocardial tissue of the patient was substantially lower (103 ± 7 ng/mg protein) than in control myocardial tissue (35 800 ± 2860 ng/mg protein). Immunoreactive CK-M in the patient tissue sample was 0.3% of the value for the control sample. CK-M mRNA was 53-fold less in the patient sample compared with the control. This very low expression of CK-M mRNA was considered to be the primary reason for CK-M deficiency. Direct sequencing revealed a point mutation at residue 54 in exon 2, which was specific for the patient. No other abnormalities were found in the CK-M gene of the patient.
Conclusions: This report identifies a molecular abnormality in human CK deficiency and discusses the physiologic relevance of CK-M.
|
Introduction
|
|---|
Creatine kinase [(CK)
1
; EC2.7.3.2] is an 82-kDa protein consisting of two subunits, CK-muscle (CK-M) and -brain (CK-B). Three isoenzymes, CK-MM, CK-MB, and CK-BB, are formed by hybridization of CK-M and -B subunits (1). CK plays a major role in fast muscle contraction by supplying creatine phosphate, which is used for ATP production, especially under anaerobic conditions. Increased CK activity accompanied by the appearance of CK-MB isoenzyme is considered to be a most useful tool in the diagnosis of acute myocardial infarction (AMI) (2). In the only case report of human CK deficiency, in which the patient did not have a definitive muscular involvement, the mechanism(s) of CK deficiency was not investigated (3). In this report, however, we describe 56-year-old female who complained of chest pain with typical clinical findings for AMI, except for the absence of CK-MB isoenzyme activity and the absence of increased total CK activity. An autopsy confirmed that the patient suffered from AMI. Thus the experiments in this study were designed to clarify the cause of the lack of total CK activity in this patient. We identify, for the first time, the molecular mechanism that may have accounted for the major reduction in CK mRNA, which led to the deficiency in CK protein expression.
|
case report
|
|---|
A 56-year-old female was admitted in a state of shock to the emergency room with chest pain of 1-day duration. The patient had been well until a day before admission, except for mild diabetes, which had not required any medication. Clinical symptoms and the electrocardiogram findings (increased S-T and terminal T inversion on II, III, and aVF leads; S-T depression on V1-V4 leads) indicated that the patient suffered a severe AMI of the posterior wall. Laboratory data demonstrated inconsistent findings with this diagnosis. Total activities of the non-cardiac-specific enzymes lactate dehydrogenase (LDH) and aspartate aminotransferase were substantially increased (6900 U/L and 2550 U/L, respectively; the reference intervals for LDH and aspartate aminotransferase were 200–400 U/L and 8–40 U/L, respectively). However, the flipped pattern of LDH-1 and LDH-2 was present, with a ratio of 1.72. No increase of serum CK activity (37 U/L; reference interval, 15–130 U/L) nor any CK-MB activity was detected. Soon after admission, an intraaortic balloon pump was placed to treat the patient for cardiogenic shock. The percutaneous transluminal coronary angioplasty was unsuccessful. On the 5th hospital day, serum CK activity had dropped to 11 U/L, whereas LDH and aspartate aminotransferase activities were 2055 and 70 U/L, respectively. The patient died on the 11th hospital day, and an autopsy was performed. Pathologic studies confirmed the infero-postlateral wall infarction of the heart. The patient had two daughters by normal delivery, neither of whom had experienced any muscular or cardiac symptoms.
|
Materials and Methods
|
|---|
The studies presented here were performed in muscle samples and sera after family members of the patient and a nonrelated control had given their approval on behalf of each. Informed consent was also obtained from healthy volunteers, from whom DNA samples were obtained and analyzed for the point mutation of CK.
immunoblotting for the detection of ck-m subunit
Right ventricular cardiac tissue, skeletal muscle (pectoralis major muscle), and smooth muscle (muscle layer of the rectum) from the patient were obtained 4 h after death and stored at -80 °C for 1 week before examination. The control tissues were obtained from a nonrelated patient who had died of acute myelogenous leukemia. To identify the CK-M protein expression, 15 µg of homogenates from cardiac and skeletal muscles of the patient and from the control, along with purified human CK-MM (BiosPacific) were immunoblotted with polyclonal goat anti-CK-M (BiosPacific). A gel prepared in parallel was stained with Coomassie Brilliant Blue G-250 (Bio-Rad) to ensure that equivalent amounts of proteins were electrophoresed on each lane.
determination of total ck, ck isoenzyme, and ck subunit activities
Total CK activity was determined by the reverse reaction with NADH production (CK-NAC; Boehringer). CK isoenzymes were separated on agarose films (CK isoenzyme gel 8; Corning) and the enzyme activity of each isoenzyme was determined with Cardiotrack CK (Corning) according to the manufacturer’s instructions. Total CK activities were measured on 10 different parts each of right ventricular cardiac tissue, skeletal muscle (pectoralis major muscle), and smooth muscle (muscle layer of the rectum) from the patient and control. Immunoreactive CK-M and CK-B subunits were measured on 5 different parts each of right ventricular cardiac tissue, skeletal muscle, and smooth muscle from the patient and control by the sensitive sandwich enzyme immunoassay method previously described (4)(5).
immunohistochemical detection of ck-m subunit
Patient and control pectoralis major muscle and cardiac muscle (10 g each) were fixed in 200 mL/L formalin for 15 h at room temperature. Sections of 4-µm thickness were stained with rabbit anti-human CK-M antibody (Ab), which was a kind gift from Dr. Kato (Department of Biochemistry, Institute for Developmental Research, Aichi Prefectural Colony, Kamily, Kasugai, Aichi, Japan) (4), followed by visualization with the aid of alkaline phosphatase-conjugated goat anti-rabbit IgG (Pierce Chemical Co.) and p-nitrophenyl phosphate (Pierce) as a substrate.
extraction of genomic dna and southern blot analysis of ck-m gene
After the proteinase K digestion, high-molecular weight genomic DNA was extracted from the pectoris major muscles of both the patient and the control. DNA from each sample (5 µg each) was digested with the restriction enzymes EcoRI, BamHI, HindIII, or TaqI (Boehringer Mannheim), and Southern hybridization was performed with a 32P-labeled CK-M cDNA probe obtained from the ATCC (6).
determination of ck-m and ß-actin mrna expression by semiquantitative reverse transcription-pcr
Total RNA was prepared from the cardiac muscle of the patient and the control by the single-step method described by Chomczynski and Sacchi (7). The first-strand cDNA was synthesized with the cDNA Synthesis Kit (Boehringer Mannheim) according to the manufacturer’s instructions. The quality of the cDNA was checked by PCR amplification of a so-called "housekeeping" gene, ß-actin. The expected size of the PCR product for ß-actin was 305 bp. PCR primers for the CK-M gene amplification were designed by Bailly et al. (8). A set of primers, nos. 1 and 16, was used for the amplification of the entire open reading frame of CK-M mRNA (9), with an expected size of the PCR product of 1378 bp. The amplification reaction was terminated during the exponential phase, and one-tenth of the PCR mixture was electrophoresed on a 3% (w/v) NuSieve 3:1 agarose gel (FMC BioProducts) followed by ethidium bromide staining. The amount of each PCR product was compared by densitometric measurement of the band (Atto Densitograph; Atto). PCR quantification of ß-actin was used to normalize the differences in cDNA quantity between samples. Previous examination revealed that up to a twofold difference between two independent quantifications of the same sample was not significant (10) (data not shown).
sequencing of the ck-m gene
Three sets of primers (nos. 1 and 5, 4 and 9, and 10 and 16) were used to amplify exons 1–3, 4–5, and 6–8, respectively, of the CK-M cDNA from the cardiac muscle of the patient (8). We purified each PCR product and determined the DNA sequence directly using the Taq DyeDeoxy Terminator Cycle Sequence reagent set (Applied Biosystems) according to the manufacturer’s instructions. Sequencing gel electrophoresis and the data analyses were performed on a DNA sequencer (Model 373 A; Applied Biosystems).
restriction fragment length polymorphism analysis of pcr products for genomic dna from healthy controls
As shown in the Results section, an A
G transition was found in exon 2 of the CK-M gene of the patient, which eliminated the restriction-recognition sequence for the restriction enzyme Tth111I. To investigate the occurrence and frequency of this mutation in the healthy population, genomic DNA was extracted from the peripheral blood mononuclear cells of nonrelated healthy volunteers (58 males and 50 females). Exon 2 of CK-M was amplified with primer nos. 2 and 3 (8), and one-half of the PCR products was digested by Tth111I (Boehringer Mannheim) at 65 °C for 1 h. Undigested and digested PCR products (10 µL each) were electrophoresed on a 3% (w/v) NuSieve 3:1 agarose gel and examined by ethidium bromide staining.
|
Results
|
|---|
The patient’s serum CK activity was low and did not increase during the entire disease course, whereas no CK-MB isoenzyme activity was detected. As shown in Table 1
, total CK activity of the patient’s tissues was 1/10 for skeletal muscle, 1/35 for cardiac muscle, and 1/24 for smooth muscle compared with those of the control tissues. The patient’s CK-B was decreased in cardiac and smooth muscles compared with the control. Although the patient’s skeletal muscle CK-B was higher than that of the control, some of skeletal muscle CK-M and CK-B of the patient was only 
2% of the value for the control.
On the immunoblot with anti-human CK-M shown in Fig. 1A
, the control skeletal and cardiac muscles demonstrated single bands of 43 kDa (lanes 3 and 5, respectively), which corresponded to the band from the purified CK-M protein (lane 1). No bands appeared in the skeletal and cardiac muscle samples from the patient (lanes 2 and 4, respectively). Coomassie Brilliant Blue staining of the gel with sodium dodecyl sulfate–polyacrylamide gel electrophoresis prepared in parallel confirmed that equivalent amounts of total protein were loaded on each lane (data not shown).
View larger version (20K):
[in this window]
[in a new window]
|
Figure 1. Immunoblotting for CK-M of the muscle tissue extracts and CK isoenzyme study of sera on agarose film.
(A), immunoblotting for CK-M. Lane 1, purified human CK-M; lane 2, cardiac muscle extract from the patient; lane 3, cardiac muscle extract from the control; lane 4, skeletal muscle from the patient; lane 5, skeletal muscle extract from the control. (B), CK isoenzyme study on agarose film. Top panel, control sera; bottom panel, patient sera. Saline, control absorption with saline; anti-CK-M, absorption with anti-human CK-M Ab.
|
|
Serum and myocardial CK isoenzymes from the control and patient were separated on an agarose film (Fig. 1B
). Serum CK-MM activity was substantially reduced, and no serum CK-MB activity was detected in the patient sample. Because of the great reduction of CK activity, it was necessary to apply 30-fold more of the protein from the patient sample on the gel to visualize the bands. Consistent with the CK activities (Table 1
) and immunoblotting results (Fig. 1A
), CK-MB in cardiac muscles was detected in the patient sample, but its activity was substantially reduced. There was essentially no detectable CK-MM band in the cardiac muscle of the patient. CK-MM was the major component of the CK isoenzymes in the control cardiac muscle (data not shown). CK-BB was not visible in the control and patient samples as expected. As shown in Fig. 1B
, the addition of anti-human CK-M Ab completely eliminated the control serum CK-MM. The Ab also eliminated the CK-MB band of the control serum, presumably because of the reactivity of the Ab to the CK-M component of CK-MB isoenzyme. In the patient samples, however, the faint CK-MM band in serum was not completely adsorbed by the Ab, suggesting the existence of the dimer form, mitochondrial CK (CK-mit). In the immunohistochemical examination shown in Fig. 2
, the control myocardium yielded positive staining (Fig. 2A
), whereas the anti-human CK-M Ab did not detect the CK-M protein in the heart muscle of the patient (Fig. 2B
).
View larger version (141K):
[in this window]
[in a new window]
|
Figure 2. Immunohistochemical detection of CK-M subunit (original magnification, x400).
Sections of myocardium of the control (A) and the patient (B) were stained with anti-CK-M, followed by visualization by alkaline phosphatase and p-nitrophenyl phosphate.
|
|
To identify the underlying molecular mechanism of this deficiency, we first performed Southern blot analysis for the CK-M gene using the genomic DNA of muscles extracted from the patient and control. The blot did not show any major abnormalities on the genomic DNA for CK-M of the patient (Fig. 3
). We next examined the CK-M mRNA expression to determine whether the observed defect in CK-M protein expression was attributable to a transcriptional abnormality. During exponential PCR amplification, cDNA from the myocardium of the patient did yield a faint band for the CK-M gene (Fig. 4
, top panel), whereas the ß-actin expression in the patient sample was comparable to that of the control (Fig. 4
, lower panel). Two independent quantifications with the applied mRNA amount normalized by means of ß-actin expression revealed that the patient’s CK-M mRNA was 68.2- and 37.7-fold (mean, 53-fold) lower than that of the control.
View larger version (79K):
[in this window]
[in a new window]
|
Figure 3. Southern blot analysis of CK-M gene.
Genomic DNAs from pectoral muscles of both the control and the patient were digested with the restriction enzymes shown, and the Southern blot hybridization was performed with 32P-labeled CK-M cDNA as a probe. E, EcoRI; B, BamHI; H, HindIII; T, TaqI.
|
|
View larger version (40K):
[in this window]
[in a new window]
|
Figure 4. Semiquantitative reverse transcription–PCR analysis of CK-M gene expression in cardiac muscle.
Top panel, CK-M; bottom panel, ß-actin.
|
|
Direct sequencing of the whole CK-M cDNA, as shown in Fig. 5
, identified a single nucleotide transition of AG in exon 2, which led to the amino acid substitution of glycine (GGC) for aspartate (GAC; wild type) at residue 54. To determine whether the single nucleotide transition found in the patient mRNA was a polymorphism of the CK-M gene, the genomic DNA sequences from 108 healthy volunteers (58 males and 50 females) were examined. PCR-amplified fragments of exon 2 of CK-M DNA were digested by Tth111I because the mutation in the corresponding sequence should cause the destruction of the restriction site of the enzyme. All of the DNA sequences tested were successfully digested by the restriction enzyme (data not shown), which confirmed that the nucleotide transition observed was a point mutation and specific for the patient.
View larger version (37K):
[in this window]
[in a new window]
|
Figure 5. cDNA sequencing of the CK-M gene.
A single nucleotide transition of AG found at residue 54 in presumably the fourth  helix led to the amino acid change of wild-type aspartate (GAC; panel A) to glycine (GGC; panel B). The triple nucleotides at residue 54 are underlined.
|
|
|
Discussion
|
|---|
We identified the transition in exon 2 of the CK gene of the patient where adenine was replaced by guanine (GACGGC), leading to the amino acid substitution with nonpolar neutral glycine of acidic aspartate (wild type). This mutation was specific for our patient because none of the DNAs derived from 108 nonrelated healthy volunteers showed any abnormality at this nucleotide position, as evidenced by the successful restriction digestion of PCR products (data not shown).
The gene for CK-M on human chromosome 19q13.2–19q13.3 is one of the most tightly linked markers of myotonic dystrophy (DM) (11)(12). Bailly et al. (8) reported that sequencing of the CK-M cDNA from the skeletal muscle of an individual with DM revealed two novel polymorphisms but no translationally significant mutation. They concluded that, in light of genetic homogeneity shown to date for DM, a defect in the coding segment of the CK-M gene is probably not a cause in all cases of DM. Thus, evidence is lacking that mutations in the CK gene may be the cause of the muscle diseases (13). In this regard, the generation and analysis of CK-M-deficient animals are of great importance for an understanding of the true physiologic roles of CK. CK-M-deficient mice were first described by van Deursen et al. (14). Similar to our case, the mutant mice were fertile and appeared to have no abnormalities. Although a detailed examination of the muscular system of the mutant mice revealed the inability to perform the burst activity; phosphocreatine and ATP concentrations appeared normal in CK-M-deficient skeletal muscles. In addition, the recovery rates of phosphocreatine and inorganic phosphoric acid concentrations after muscular stimulation had stopped were also comparable, suggesting that the hydrolyzed phosphocreatine was replenished via a CK-mit reaction.
CK-mit is a distinct isoenzyme of CK that is associated with the outer face of the mitochondrial inner membrane and is functionally linked to oxidative phosphorylation (15). CK-mit has been detected in normal human heart and liver (16), as well as sera from patients with AMI (17). More than 90% of tissue CK-mit is octameric (18) and exhibits cathodal migration on electrophoresis because of its positive charge, whereas CK-BB and CK-MB are negatively charged and CK-MM is neutral (19)(20). However, Kanemitsu et al. (16) showed that serum octameric CK-mit displayed a tendency to dissociate into stable dimers, which stayed in the same position as CK-MM during electrophoresis. On the agarose film electrophoresis (Fig. 1B
), a faint band remained at the position of CK-MM in the serum of the patient treated with the CK-M Ab. The finding that the CK-MM of the control serum, which was much more abundant than that of the patient, was completely adsorbed by the anti-CK-M Ab suggests that the residual CK-MM of the patient was also adsorbed. Therefore, this faint band at the CK-MM position in the serum of the patient may represent the CK-mit of dimeric form. We did not reliably determine the CK-mit activity in the cardiac tissue of the patient, mainly because of the limited availability of samples. It is reported, however, that in normal cardiac cells, the mitochondrial component contains 30–40% of the cardiac cell CK activity (21). We believe that CK-mit compensated for most of the CK-M functions in our patient. Alternatively, CK function may be compensated by the different kinase(s). Dzeja et al. (22) reported an apparent compensatory shift in phosphotransfer catalysis from the CK to the adenylate kinase system with increasing muscle contraction or graded chemical inhibition of CK activity. Thus it is possible that the adenylate kinase system may, in part, have taken over the compromised CK function in our patient.
The degree of expression of a gene is affected not only by the efficiency of transcription and/or translation, but also by the stability of mRNA (23). Because a poly(A) tail and 3'-untranslated region (UTR) are considered important for determining the fate of mRNA, we determined the 5'-UTR sequence up to 975 bp upstream of the initiation codon of CK-M mRNA and the 3'-UTR sequence 130 bp downstream of open reading frame. We found no differences in the 3'-UTR, but in the 5'-UTR, we identified 14 nucleotide differences from the sequence reported by Trask et al. (9). None of the differences in the 5'-UTR, however, was in the promoter or enhancer regions (data not shown). We also searched for E2A gene abnormalities because E2A is considered one of the essential factors for the transcription of many genes, including CK-M (24), but Southern blot analysis revealed no evident abnormality on E2A DNA (data not shown). Although the precise molecular mechanism(s) leading to the extremely low expression of CK-M mRNA in our case are unclear, the apparent absence of any abnormalities in the promoter and enhancer regions and the 3'-UTR, as well as in the transcription factor E2A gene, suggests that the observed point mutation in exon 2 of CK-M mRNA is responsible for the deficient CK-M protein expression. It will be of interest to see whether the site-directed mutagenesis of CK-M gene reproduces the CK-M deficiency similar to our patient, or whether the CK-M expression can be reconstituted when the mutated CK-M gene is introduced into the CK-M deficient mice to mimic our case. Such experiments may lead to a better understanding of the true physiologic and pathologic roles of CK in the human muscular system.
The diagnosis of AMI in our patient was determined by the combination of clinical symptoms, electrocardiogram, and non-cardiac-specific biochemical markers. Shibuya et al. (3) reported a case of 46-year-old male in whom serum CK was extremely low and CK-M was absent. The patient was initially diagnosed as having a myocardial ischemia from his clinical symptoms, but further medical tests showed no evidence of ischemia. Recent studies have revealed that cardiac troponin I is uniquely specific for the heart and that cardiac troponin T if measured by the Roche cardiac troponin T assay is not interfered by the isoforms expressed in skeletal muscle (25). Furthermore, McLaurin et al. (26) reported that cardiac troponin I and cardiac troponin T concentrations were within normal limits in patients without the recent myocardial injury, in whom CK-MB activities were increased. Thus, cardiac troponin I and T should be superior to measurement of CK-MB for detecting cardiac damage. The measurement of cardiac troponin I and T would have been useful in our patient and the patient of Shibuya et al. (3) to make accurate clinical evaluation of recent myocardial injury.
|
Acknowledgments
|
|---|
This work is supported in part by the Kobe City Fund for the Promotion of Medical Research. We thank Dr. Tomoko Nakamura-Wada and Mari Hyakuta (Kobe University) for their helpful discussion, and Nobuhide Hayashi (Kobe University) and Jan K. Visscher (English Language Consultant) for editorial assistance and preparation of the manuscript.
|
Footnotes
|
|---|
1 Nonstandard abbreviations: CK, creatine kinase; CK-M and -B, CK-muscle and -brain, respectively; AMI, acute myocardial infarction; Ab, antibody; UTR, untranslated region; CK-mit, mitochondrial CK; and DM, myotonic dystrophy. 
|
References
|
|---|
-
Dawson DM, Eppenberger HM, Kaplan NO. Creatine kinase: evidence for a dimeric structure. Biochem Biophys Res Commun 1965;21:346-353.[Web of Science][Medline]
[Order article via Infotrieve]
-
Katz IA, Irwig L, Vinen JD, March L, Wyndham LE, Luu T, et al. Biochemical markers of acute myocardial infarction: strategies for improving their clinical usefulness. Ann Clin Biochem 1998;35:393-399.
-
Shibuya J, Matsumoto T, Takahashi K, Sugisawa K, Yasutomi N, Kawashima S, et al. The first report of a case with acute myocardial infarction showing familial deficiency of creatine kinase. Intern Med 1992;31:611-616.[Web of Science][Medline]
[Order article via Infotrieve]
-
Kato K, Shimizu A. Highly sensitive enzyme immunoassay for human creatine kinase MM and MB isozymes. Clin Chim Acta 1986;158:99-108.[Web of Science][Medline]
[Order article via Infotrieve]
-
Kato K, Shimizu A, Ishiguro Y, Mokuno K, Ariyoshi Y, Nakajima T. Highly sensitive enzyme immunoassay for human creatine kinase BB isozyme. Clin Chim Acta 1985;150:31-40.[Web of Science][Medline]
[Order article via Infotrieve]
-
Fukutani H, Naoe T, Yoshida H, Yamamori S, Ohno R. Molecular heterogeneity of the PML gene rearrangement in acute promyelocytic leukemia: prevalence and clinical significance. Jpn J Cancer Res 1993;84:257-264.[Web of Science][Medline]
[Order article via Infotrieve]
-
Chomczynski P, Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem 1987;162:156-159.[Web of Science][Medline]
[Order article via Infotrieve]
-
Bailly J, MacKenzie AE, Leblond S, Korneluk RG. Assessment of a creatine kinase isoform M defect as a cause of myotonic dystrophy and the characterization of two novel CKMM polymorphisms. Hum Genet 1991;86:457-462.[Web of Science][Medline]
[Order article via Infotrieve]
-
Trask RV, Strauss AW, Billadello JJ. Developmental regulation and tissue-specific expression of the human muscle creatine kinase gene. J Biol Chem 1988;263:17142-17149.[Abstract/Free Full Text]
-
Koshiba M, Apasov S, Sverdlov V, Chen P, Erb L, Weisman GA, et al. Transient up-regulation of P2Y2 nucleotide receptor mRNA expression is an immediate early gene response in activated thymocytes. Proc Natl Acad Sci U S A 1997;94:831-836.[Abstract/Free Full Text]
-
Brunner HG, Korneluk RG, Coerwinkel-Driessen M, MacKenzie A, Smeets H, Lambermon HM, et al. Myotonic dystrophy is closely linked to the gene for muscle-type creatine kinase (CKMM). Hum Genet 1989;81:308-310.[Web of Science][Medline]
[Order article via Infotrieve]
-
Korneluk RG, MacKenzie AE, Nakamura Y, Dube I, Jacob P, Hunter AG. A reordering of human chromosome 19 long-arm DNA markers and identification of markers flanking the myotonic dystrophy locus. Genomics 1989;5:596-604.[Web of Science][Medline]
[Order article via Infotrieve]
-
Wyss M, Kaddurah-Daouk R. Creatine and creatinine metabolism. Physiol Rev 2000;80:1107-1213.[Abstract/Free Full Text]
-
van Deursen J, Heerschap A, Oerlemans F, Ruitenbeek W, Jap P, ter Laak H, et al. Skeletal muscles of mice deficient in muscle creatine kinase lack burst activity. Cell 1993;74:621-631.[Web of Science][Medline]
[Order article via Infotrieve]
-
Wyss M, Smeitink J, Wevers RA, Wallimann T. Mitochondrial creatine kinase: a key enzyme of aerobic energy metabolism. Biochim Biophys Acta 1992;1102:119-166.[Medline]
[Order article via Infotrieve]
-
Kanemitsu F, Kawanishi I, Mizushima J. Characteristics of mitochondrial creatine kinases from normal human heart and liver tissues. Clin Chim Acta 1982;119:307-317.[Web of Science][Medline]
[Order article via Infotrieve]
-
James GP, Harrison RL. Creatine kinase isoenzymes of mitochondrial origin in human serum. Clin Chem 1979;25:943-947.[Abstract/Free Full Text]
-
Schlegel J, Wyss M, Eppenberger HM, Wallimann T. Functional studies with the octameric and dimeric form of mitochondrial creatine kinase. Differential pH-dependent association of the two oligomeric forms with the inner mitochondrial membrane. J Biol Chem 1990;265:9221-9227.[Abstract/Free Full Text]
-
Roberts R, Grace AM. Purification of mitochondrial creatine kinase. Biochemical and immunological characterization. J Biol Chem 1980;255:2870-2877.[Abstract/Free Full Text]
-
Lee KN, Csako G, Bernhardt P, Elin RJ. Relevance of macro creatine kinase type 1 and type 2 isoenzymes to laboratory and clinical data. Clin Chem 1994;40:1278-1283.[Abstract/Free Full Text]
-
Saks VA, Kupriyanov VV, Elizarova GV, Jacobus WE. Studies of energy transport in heart cells. The importance of creatine kinase localization for the coupling of mitochondrial phosphorylcreatine production to oxidative phosphorylation. J Biol Chem 1980;255:755-763.[Free Full Text]
-
Dzeja PP, Zeleznikar RJ, Goldberg ND. Adenylate kinase: kinetic behavior in intact cells indicates it is integral to multiple cellular processes. Mol Cell Biochem 1998;184:169-182.[Web of Science][Medline]
[Order article via Infotrieve]
-
Grunberg-Manago M. Messenger RNA stability and its role in control of gene expression in bacteria and phages. Annu Rev Genet 1999;33:193-227.[Web of Science][Medline]
[Order article via Infotrieve]
-
Edmondson DG, Olson EN. Helix-loop-helix proteins as regulators of muscle-specific transcription. J Biol Chem 1993;268:755-758.[Free Full Text]
-
Apple FS. The specificity of biochemical markers of cardiac damage: a problem solved. Clin Chem Lab Med 1999;37:1085-1089.[Web of Science][Medline]
[Order article via Infotrieve]
-
McLaurin M, Apple FS, Henry TD, Sharkey SW. Cardiac troponin I and T concentrations in patients with cocaine-associated chest pain. Ann Clin Biochem 1996;33:183-186.
The following articles in journals at HighWire Press have cited this article:
|
|
|
|
 
L. M. Brewster, G. Mairuhu, N. R. Bindraban, R. P. Koopmans, J. F. Clark, and G. A. van Montfrans
Creatine Kinase Activity Is Associated With Blood Pressure
Circulation,
November 7, 2006;
114(19):
2034 - 2039.
[Abstract]
[Full Text]
[PDF]
|
|
|
Top
Abstract
Introduction
