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Evolutionary hypothesis of the Mevalonate Kinase Deficiency
Medical Hypotheses 80 (2013) 67–69
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Evolutionary hypothesis of the Mevalonate Kinase Deficiency J. Vuch a, A. Marcuzzi a,⇑, A.M. Bianco a, A. Tommasini a, V. Zanin a, S. Crovella a,b a b
Institute for Maternal and Child Health-IRCCS ‘‘Burlo Garofolo’’, Trieste, Italy Universitary Department of Clinical Medical Sciences, Surgical and Health, University of Trieste, Italy
a r t i c l e
i n f o
Article history: Received 16 February 2012 Accepted 25 October 2012
a b s t r a c t Mevalonate Kinase Deficiency (MKD) is an autosomal-recessively inherited disorder of cholesterol biosynthesis with higher prevalence in the Netherlands and other North European countries. MKD is due to mutations in the second enzyme of mevalonate pathway (mevalonate kinase, MK/MVK) which results in reduced enzymatic activity and in the consequent shortage of downstream compounds. In most severe cases the deregulation of mevalonate pathway is associated with a decrease in serum cholesterol. More than 100 pathological mutations have been described in the MVK gene so far, and a founder effect has been hypothesized as responsible for the diffusion of the most frequent disease-associated mutations. In the acute phase of disease, patients affected with MKD present low cholesterol levels comparable to their basal physiologic conditions, already characterized by lower cholesterol levels when compared to healthy individuals. Low cholesterol levels are widely known to correlate with the reduction of cardiovascular events. We hypothesize a selective advantage for heterozygote carriers of the most frequent MVK mutations in those countries where the diet is characterized by high consumption of saturated animal fats rich in cholesterol. This could explain the maintenance in North European population of the main mutations leading to MKD and the distribution world-wide of these mutations that followed the migrations of North European populations. Ó 2012 Elsevier Ltd. All rights reserved.
Introduction
Discussion
Mevalonate Kinase Deficiency (MKD) is an autosomal-recessive inherited disease (OMIM #610377), more frequent in the population from Northern Europe [1], caused by mutations in the MVK gene (12q24.11). MVK encodes for mevalonate kinase (MK), the second enzyme of the mevalonate pathway (Fig. 1), the biochemical pathway leading to the synthesis of cholesterol. The impairment of MK originates a shortage of downstream intermediates in mevalonate pathway and is responsible for the development of recurrent acute inflammatory episodes, involving lymphoid organs, skin and abdomen [2]. When the frequency of recessive-inherited disease strongly impacting the phenotype of mutated homozygotes by reducing their fitness, is conserved for generations, the maintaining the disease allele in the population is possibly explainable by the selective heterozygous advantage, established in response to a specific environmental pressure. Here we hypothesize a selective advantage for heterozygous carriers of the more frequent MVK mutations in populations, including the North European ones, with high consumption of animal fats rich in cholesterol.
When analyzing the genetic defect leading to MKD we observe that many patients are compound heterozygotes [1] for MVK more common mutation, the V377I (c.1129G>A), a missense mutation found in 32.08% of Caucasian MKD patient population [3]. Other frequent MVK mutations such as I268T (c.803T>C) (in 14%, 15% of the Caucasian MKD patient population) [3] and H20P (c.59A>C) (in 5.66% of the Caucasian MKD patient population) have been found mainly in individuals from Northern Europe [3]. The Dutch group of Simon et al. [1] described a founder effect for the mutation V377I, explaining its distribution worldwide, through successive migrations from the Netherlands to other countries in the recent history (Fig. 2). The founder effect hypothesized for the V377I mutation [1] could account for the worldwide diffusion of this mutation from a common ancestor, and the same selective mechanism can be figured out to explain the spread of the other MVK frequent mutations, namely I268T (c.803T>C) and H20P (c.59A>C), associated with MKD characterized by phenotypes with different severity [3]. MKD is characterized by auto-inflammatory symptoms and different degrees of disease severity related to the residual activity of MK were observed, ranging from Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS, OMIM #260920) with a 1–8% residual MK activity to mevalonic aciduria (MA, OMIM #610377)
⇑ Corresponding author. Tel./fax: +39 0403785422. E-mail address: [email protected] (A. Marcuzzi). 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2012.10.016
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J. Vuch et al. / Medical Hypotheses 80 (2013) 67–69
Fig. 1. Schematic representation of mevalonate pathway. The enzymes (HMG-CoA reductase and mevalonate kinase) are indicated along the pathway in bold characters.
Fig. 2. Dutch migrations in the last centuries (from 17th to 20th). Number of migrants are indicated in the map. Migrations to: Antilles from 17th to 20th centuries; East-India 19th century; USA, Canada, Australia, South Africa, Argentina and Brazil 20th century. The Dutch migration to Germany, began after the outbreak of World War I, while to Belgium emigration occurred in two waves, in 1800 and after 1900 [11].
heterozygous carriers of MVK mutations, as well as homozygous individuals with a mild phenotype, could have a selective advantage correlated with cholesterol levels reduction. In fact the heterozygous carrier could present a partial impairment of the MK pathway leading to partial HMG-CoA reductase inhibition decreasing the cholesterol synthesis. The higher frequency of MVK mutations in Northern Europe and the consequent increased incidence of the disease [9] could be related to the selective advantage of heterozygous carriers in a population where the consumption of saturated animal fats rich in cholesterol is relevant. For example, North European countries such as Finland and Netherlands have diets with an elevated presence of saturated fat, more than double the Mediterranean countries like Greece and Italy and four times more than Japan [7]. It is noteworthy that Dutch emigrants maintained their alimentary habits even in tropical countries (i.e. Java and East Indies) and it has been demonstrated that their blood cholesterol levels were higher with respect to the native populations, due to the different diets [7]. Unfortunately no data concerning the distribution of the MVK gene’s mutations in different ethnic groups are available because, being a poorly understood disease with a variable phenotype MKD is probably under-diagnosed. In conclusion, migrations occurred in the recent history and the consequent founder effect, already described for the V377I mutation [1], together with the advantage of MVK mutations heterozygous carriers could be hypothesized as the selective genetic engine responsible for the different world-wide distribution of MVK mutations and frequency of the disease. The diffusion of MVK diseaseassociated mutations could be related to the advantage of the heterozygous carriers, able to better survive (and having higher fitness) in populations characterized by cholesterol-rich diet and consequent increased cardiovascular disease rate. Trying to raise some criticism to our hypothesis, we are aware that cardiovascular disease occurs in general after 40 years of age. So, the difference in terms of fitness between heterozygous carriers of MVK mutations and individuals with wild-type genotype could be not so relevant. Anyway the quality of life in terms of health will be better in individuals with a ‘‘cholesterol free’’ genetic background, moreover they are expected to have a longer life. This could bring a benefit to ‘‘the grandparents advantage theory’’, to relatives because the elder can bring experience and take care of their children [10]. In conclusion, we do hope that, with the improvement of MKD disease diagnostic algorithms, more information will be available on allele and genotype frequencies of MVK mutations in different ethnic groups in order to confirm our hypothesis.
Conflict of interest statement None declared.
in which MK activity is below the level of detection. HIDS, also called Dutch fever, is almost a benign condition in which patients have recurrent episodes of fever associated with inflammatory symptoms [4]; MA is a more severe condition characterized, in addition to febrile and inflammatory episodes, by psychomotor retardation, dysmorphic features, ataxia, cerebellar atrophy, and patients may die in early childhood [4]. MKD patients in the acute phase of disease, present low cholesterol levels comparable to their basal physiologic conditions, already characterized by lower cholesterol levels when compared to healthy individuals [5,6]. Starting from this observation and knowing that the risk of heart-attack is roughly proportional to the blood cholesterol level [7] and that its reduction decreases the incidence of cardiovascular diseases [7,8], we hypothesize that
References [1] Simon A, Mariman EC, van der Meer JW, Drenth JP. A founder effect in the hyperimmunoglobulinemia D and periodic fever syndrome. Am J Med 2003;114:148–52. [2] Kuijk LM, Beekman JM, Koster J, Waterham HR, Frenkel J, Coffer PJ. HMG-CoA reductase inhibition induces IL-1beta release through Rac1/PI3K/PKBdependent caspase-1 activation. Blood 2008;112:3563–73. [3] Mandey SH, Schneiders MS, Koster J, Waterham HR. Mutational spectrum and genotype–phenotype correlations in mevalonate kinase deficiency. Hum Mutat 2006;27:796–802. [4] Haas D, Hoffmann GF. Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome. Orphanet J Rare Dis 2006;1:13. [5] Simon A, Bijzet J, Voorbij HA, Mantovani A, van der Meer JW, Drenth JP. Effect of inflammatory attacks in the classical type hyper-IgD syndrome on
J. Vuch et al. / Medical Hypotheses 80 (2013) 67–69 immunoglobulin D, cholesterol and parameters of the acute phase response. J Intern Med 2004;256:247–53. [6] Marcuzzi A, Decorti G, Pontillo A, Ventura A, Tommasini A. Decreased cholesterol levels reflect a consumption of anti-inflammatory isoprenoids associated with an impaired control of inflammation in a mouse model of mevalonate kinase deficiency. Inflamm Res 2010;59:335–8. [7] Steinberg D. Thematic review series: the pathogenesis of atherosclerosis: an interpretive history of the cholesterol controversy, part III: mechanistically defining the role of hyperlipidemia. J Lipid Res 2005;46: 2037–51.
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[8] Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97:1837–47. [9] Houten SM, van Woerden CS, Wijburg FA, Wanders RJ, Waterham HR. Carrier frequency of the V377I (1129G > A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet 2003;11:196–200. [10] Caspari R. The evolution of grandparents. Sci Am 2011;305:44–9. [11] Zeegers MP, van Poppel F, Vlietinck R, Spruijt L, Ostrer H. Founder mutations among the Dutch. Eur J Hum Genet 2004;12:591–600.
Contents lists available at SciVerse ScienceDirect
Medical Hypotheses journal homepage: www.elsevier.com/locate/mehy
Evolutionary hypothesis of the Mevalonate Kinase Deficiency J. Vuch a, A. Marcuzzi a,⇑, A.M. Bianco a, A. Tommasini a, V. Zanin a, S. Crovella a,b a b
Institute for Maternal and Child Health-IRCCS ‘‘Burlo Garofolo’’, Trieste, Italy Universitary Department of Clinical Medical Sciences, Surgical and Health, University of Trieste, Italy
a r t i c l e
i n f o
Article history: Received 16 February 2012 Accepted 25 October 2012
a b s t r a c t Mevalonate Kinase Deficiency (MKD) is an autosomal-recessively inherited disorder of cholesterol biosynthesis with higher prevalence in the Netherlands and other North European countries. MKD is due to mutations in the second enzyme of mevalonate pathway (mevalonate kinase, MK/MVK) which results in reduced enzymatic activity and in the consequent shortage of downstream compounds. In most severe cases the deregulation of mevalonate pathway is associated with a decrease in serum cholesterol. More than 100 pathological mutations have been described in the MVK gene so far, and a founder effect has been hypothesized as responsible for the diffusion of the most frequent disease-associated mutations. In the acute phase of disease, patients affected with MKD present low cholesterol levels comparable to their basal physiologic conditions, already characterized by lower cholesterol levels when compared to healthy individuals. Low cholesterol levels are widely known to correlate with the reduction of cardiovascular events. We hypothesize a selective advantage for heterozygote carriers of the most frequent MVK mutations in those countries where the diet is characterized by high consumption of saturated animal fats rich in cholesterol. This could explain the maintenance in North European population of the main mutations leading to MKD and the distribution world-wide of these mutations that followed the migrations of North European populations. Ó 2012 Elsevier Ltd. All rights reserved.
Introduction
Discussion
Mevalonate Kinase Deficiency (MKD) is an autosomal-recessive inherited disease (OMIM #610377), more frequent in the population from Northern Europe [1], caused by mutations in the MVK gene (12q24.11). MVK encodes for mevalonate kinase (MK), the second enzyme of the mevalonate pathway (Fig. 1), the biochemical pathway leading to the synthesis of cholesterol. The impairment of MK originates a shortage of downstream intermediates in mevalonate pathway and is responsible for the development of recurrent acute inflammatory episodes, involving lymphoid organs, skin and abdomen [2]. When the frequency of recessive-inherited disease strongly impacting the phenotype of mutated homozygotes by reducing their fitness, is conserved for generations, the maintaining the disease allele in the population is possibly explainable by the selective heterozygous advantage, established in response to a specific environmental pressure. Here we hypothesize a selective advantage for heterozygous carriers of the more frequent MVK mutations in populations, including the North European ones, with high consumption of animal fats rich in cholesterol.
When analyzing the genetic defect leading to MKD we observe that many patients are compound heterozygotes [1] for MVK more common mutation, the V377I (c.1129G>A), a missense mutation found in 32.08% of Caucasian MKD patient population [3]. Other frequent MVK mutations such as I268T (c.803T>C) (in 14%, 15% of the Caucasian MKD patient population) [3] and H20P (c.59A>C) (in 5.66% of the Caucasian MKD patient population) have been found mainly in individuals from Northern Europe [3]. The Dutch group of Simon et al. [1] described a founder effect for the mutation V377I, explaining its distribution worldwide, through successive migrations from the Netherlands to other countries in the recent history (Fig. 2). The founder effect hypothesized for the V377I mutation [1] could account for the worldwide diffusion of this mutation from a common ancestor, and the same selective mechanism can be figured out to explain the spread of the other MVK frequent mutations, namely I268T (c.803T>C) and H20P (c.59A>C), associated with MKD characterized by phenotypes with different severity [3]. MKD is characterized by auto-inflammatory symptoms and different degrees of disease severity related to the residual activity of MK were observed, ranging from Hyperimmunoglobulinemia D and periodic fever syndrome (HIDS, OMIM #260920) with a 1–8% residual MK activity to mevalonic aciduria (MA, OMIM #610377)
⇑ Corresponding author. Tel./fax: +39 0403785422. E-mail address: [email protected] (A. Marcuzzi). 0306-9877/$ - see front matter Ó 2012 Elsevier Ltd. All rights reserved. http://dx.doi.org/10.1016/j.mehy.2012.10.016
68
J. Vuch et al. / Medical Hypotheses 80 (2013) 67–69
Fig. 1. Schematic representation of mevalonate pathway. The enzymes (HMG-CoA reductase and mevalonate kinase) are indicated along the pathway in bold characters.
Fig. 2. Dutch migrations in the last centuries (from 17th to 20th). Number of migrants are indicated in the map. Migrations to: Antilles from 17th to 20th centuries; East-India 19th century; USA, Canada, Australia, South Africa, Argentina and Brazil 20th century. The Dutch migration to Germany, began after the outbreak of World War I, while to Belgium emigration occurred in two waves, in 1800 and after 1900 [11].
heterozygous carriers of MVK mutations, as well as homozygous individuals with a mild phenotype, could have a selective advantage correlated with cholesterol levels reduction. In fact the heterozygous carrier could present a partial impairment of the MK pathway leading to partial HMG-CoA reductase inhibition decreasing the cholesterol synthesis. The higher frequency of MVK mutations in Northern Europe and the consequent increased incidence of the disease [9] could be related to the selective advantage of heterozygous carriers in a population where the consumption of saturated animal fats rich in cholesterol is relevant. For example, North European countries such as Finland and Netherlands have diets with an elevated presence of saturated fat, more than double the Mediterranean countries like Greece and Italy and four times more than Japan [7]. It is noteworthy that Dutch emigrants maintained their alimentary habits even in tropical countries (i.e. Java and East Indies) and it has been demonstrated that their blood cholesterol levels were higher with respect to the native populations, due to the different diets [7]. Unfortunately no data concerning the distribution of the MVK gene’s mutations in different ethnic groups are available because, being a poorly understood disease with a variable phenotype MKD is probably under-diagnosed. In conclusion, migrations occurred in the recent history and the consequent founder effect, already described for the V377I mutation [1], together with the advantage of MVK mutations heterozygous carriers could be hypothesized as the selective genetic engine responsible for the different world-wide distribution of MVK mutations and frequency of the disease. The diffusion of MVK diseaseassociated mutations could be related to the advantage of the heterozygous carriers, able to better survive (and having higher fitness) in populations characterized by cholesterol-rich diet and consequent increased cardiovascular disease rate. Trying to raise some criticism to our hypothesis, we are aware that cardiovascular disease occurs in general after 40 years of age. So, the difference in terms of fitness between heterozygous carriers of MVK mutations and individuals with wild-type genotype could be not so relevant. Anyway the quality of life in terms of health will be better in individuals with a ‘‘cholesterol free’’ genetic background, moreover they are expected to have a longer life. This could bring a benefit to ‘‘the grandparents advantage theory’’, to relatives because the elder can bring experience and take care of their children [10]. In conclusion, we do hope that, with the improvement of MKD disease diagnostic algorithms, more information will be available on allele and genotype frequencies of MVK mutations in different ethnic groups in order to confirm our hypothesis.
Conflict of interest statement None declared.
in which MK activity is below the level of detection. HIDS, also called Dutch fever, is almost a benign condition in which patients have recurrent episodes of fever associated with inflammatory symptoms [4]; MA is a more severe condition characterized, in addition to febrile and inflammatory episodes, by psychomotor retardation, dysmorphic features, ataxia, cerebellar atrophy, and patients may die in early childhood [4]. MKD patients in the acute phase of disease, present low cholesterol levels comparable to their basal physiologic conditions, already characterized by lower cholesterol levels when compared to healthy individuals [5,6]. Starting from this observation and knowing that the risk of heart-attack is roughly proportional to the blood cholesterol level [7] and that its reduction decreases the incidence of cardiovascular diseases [7,8], we hypothesize that
References [1] Simon A, Mariman EC, van der Meer JW, Drenth JP. A founder effect in the hyperimmunoglobulinemia D and periodic fever syndrome. Am J Med 2003;114:148–52. [2] Kuijk LM, Beekman JM, Koster J, Waterham HR, Frenkel J, Coffer PJ. HMG-CoA reductase inhibition induces IL-1beta release through Rac1/PI3K/PKBdependent caspase-1 activation. Blood 2008;112:3563–73. [3] Mandey SH, Schneiders MS, Koster J, Waterham HR. Mutational spectrum and genotype–phenotype correlations in mevalonate kinase deficiency. Hum Mutat 2006;27:796–802. [4] Haas D, Hoffmann GF. Mevalonate kinase deficiencies: from mevalonic aciduria to hyperimmunoglobulinemia D syndrome. Orphanet J Rare Dis 2006;1:13. [5] Simon A, Bijzet J, Voorbij HA, Mantovani A, van der Meer JW, Drenth JP. Effect of inflammatory attacks in the classical type hyper-IgD syndrome on
J. Vuch et al. / Medical Hypotheses 80 (2013) 67–69 immunoglobulin D, cholesterol and parameters of the acute phase response. J Intern Med 2004;256:247–53. [6] Marcuzzi A, Decorti G, Pontillo A, Ventura A, Tommasini A. Decreased cholesterol levels reflect a consumption of anti-inflammatory isoprenoids associated with an impaired control of inflammation in a mouse model of mevalonate kinase deficiency. Inflamm Res 2010;59:335–8. [7] Steinberg D. Thematic review series: the pathogenesis of atherosclerosis: an interpretive history of the cholesterol controversy, part III: mechanistically defining the role of hyperlipidemia. J Lipid Res 2005;46: 2037–51.
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[8] Wilson PW, D’Agostino RB, Levy D, Belanger AM, Silbershatz H, Kannel WB. Prediction of coronary heart disease using risk factor categories. Circulation 1998;97:1837–47. [9] Houten SM, van Woerden CS, Wijburg FA, Wanders RJ, Waterham HR. Carrier frequency of the V377I (1129G > A) MVK mutation, associated with Hyper-IgD and periodic fever syndrome, in the Netherlands. Eur J Hum Genet 2003;11:196–200. [10] Caspari R. The evolution of grandparents. Sci Am 2011;305:44–9. [11] Zeegers MP, van Poppel F, Vlietinck R, Spruijt L, Ostrer H. Founder mutations among the Dutch. Eur J Hum Genet 2004;12:591–600.