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PERSPECTIVE
From the Department of Molecular and Experimental
Medicine, The Scripps Research Institute, La Jolla, CA.
An African American male infant with sickle cell disease has a
devastating stroke; an African American soldier is surprised when he is
informed that he has sickle cell disease. They are both homozygous for
the same mutation. An Ashkenazi Jewish woman with Gaucher disease has a
huge spleen and severe thrombocytopenia; her older brother, homozygous
for the same 1226G glucocerebrosidase mutation, is found on routine
examination to have a barely palpable spleen tip. The fact that
clinical manifestations of genetic diseases can vary widely among
patients has been recognized for many decades. In the past, however, it
could often be attributed to the pleomorphic nature of mutations of the
same gene: the patient with severe disease, it was averred, must have a
different mutation than the one with mild disease. Even before a
precise definition of mutations could be achieved at the DNA level,
such an explanation did not serve to clarify the differences that
existed between siblings with the same autosomal recessive disease.
Such siblings must surely be carrying the same 2 disease-producing
alleles. With the advent of sequence analysis of genes, the great
extent of phenotype variation in patients with the same genotype has
come to be more fully appreciated, but understanding of why it occurs continues to be meager. It is the purpose of this review to explore some of the variations in phenotype seen by hematologists in patients with identical mutations, to indicate where some progress has been
made, and to suggest how understanding in this important area may be expanded.
(Blood. 2001;98:2597-2602) Differences in the clinical expression of the
homozygous or, in the case of X-linked genes, the hemizygous expression
of a disease state may be the result of environmental or genetic
factors or of their combination. If the data were available, the
contribution of each of these factors could be deduced from the study
of appropriate populations, as summarized in Table
1. Discordance between identical twins
would of necessity be due to environmental factors. Discordance between
siblings could be due to environmental factors or to genetic factors
unlinked to the primary disease-producing gene. Discordance among
unrelated members of the patient population could be due to
environmental factors or genetic factors, even those that may be linked
with the primary mutation, such as second mutations or differences in
the strength of the promoter. It should be remembered, however, that in
many recently arising mutations common in an ethnic group, such as the
845G6A (C282Y) mutation of hemochromatosis or the 1226 C6G (N370S)
mutation of Gaucher disease, the gene of "unrelated" members of the
population has a single common ancestor and is found in the context of
the same haplotype in all members of the population. Thus, apparently
unrelated persons may well be in the same position as siblings; barring
additional mutations occurring at the same locus even more recently
than the disease-producing mutation, they all share the same gene with
the same promoter. Although documentation of phenotypic difference
within these 3 groups among monozygotic twins, siblings, and unrelated
persons would be of great value, there are virtually no published data on this important topic. In particular, the study of monozygotic twins
would yield invaluable information about the relative contributions of
genetics and environment in phenotypic variability.
Sickle cell disease can result from the homozygous state for the
hemoglobin S mutation, from the compound heterozygous state for the
hemoglobin S and hemoglobin C mutations, and from the compound
heterozygous state for the hemoglobin S and a The homozygous state for sickle cell disease can be virtually
asymptomatic, particularly among some Arab populations, or can manifest
a devastating phenotype with repeated strokes and early death. Various
factors that may influence the severity of the disease have been
investigated. The fact that fetal cells did not sickle was discovered
in 1949, and the possibility that high levels of fetal hemoglobin in
patients might influence the disease by not interacting with sickle
hemoglobin was subsequently proposed.2 Numerous studies
have been carried out to determine whether variability in the levels of
hemoglobin F accounted for differences in the severity of the
disease,3-7 though a minimum threshold of fetal hemoglobin
may be required.3 These suggested that high levels of
fetal hemoglobin do protect against sickling. Genetic control of the
number of cells containing high levels of hemoglobin F may, therefore,
be a factor in modulating the severity of sickling, and putative
regulatory loci on chromosome 6 and the X chromosome have been
mapped.8 High levels of 2,3 diphosphoglycerate (2,3-DPG) promote sickling,9-12 and the coinheritance of even sickle
trait with pyruvate kinase deficiency, which increases 2,3-DPG levels, gave rise to a clinically significant sickling.13
The inverse relationship between Glucose-6-phosphate dehydrogenase (G6PD) is the prototype of the
interaction of a genotype with the environment. Common severe forms of
this enzyme deficiency, eg, G6PD Union, G6PD Mahidol, and G6PD
Mediterranean, are characterized by 2 main clinical manifestations, hemolytic anemia in adults and jaundice in neonates. The former can be
precipitated by drug ingestion, fava bean ingestion, or infection.16 Not long after this enzyme deficiency was
discovered, it was observed that expression of G6PD deficiency varied
markedly among women. Based on the pioneering work of
Ohno17 on the chromatin state of the 2 X chromosomes, we
suggested that there was random inactivation of one or the other X
chromosome of females,18 a phenomenon independently
proposed by Lyon19 to explain the patchy pattern of mice
with X-linked coat color mutations, the molecular basis of which has
been unraveled in recent years.20 However, even among
males there is marked variability The neonatal jaundice that occurs in G6PD-deficient infants is
not associated with increased hemolysis, and it has appeared likely
that its origin is insufficient conjugation of bilirubin with
glucuronide in the liver.16 In 1996 a polymorphism in
the promoter of the UDP glucuronosyltransferase-1 gene
(UGT1) that causes Gilbert syndrome was
identified.28 Examination of DNA from G6PD-deficient and
healthy infants disclosed that only those infants inheriting both the
G6PD-deficiency gene and the UDP glucuronosyltransferase polymorphism
had an increased tendency toward the development of severe
hyperbilirubinemia.29 Although some recent retrospective studies could not find such an effect,30,31 the original
prospective data seem robust. A similar effect of the UGT1
promoter polymorphism has now been found to produce increased jaundice
in newborns with hereditary spherocytosis32 and in adults
with hereditary spherocytosis,33 heterozygous
Clinical manifestations of Gaucher disease span an exceptionally
broad spectrum, ranging from hydrops fetalis35-37 to
incidental diagnoses in patients older than 70.38,39 A
major part of this variability is explained by different mutations of
the glucocerebrosidase gene, but even within genotypes variability is
marked. The most common Gaucher disease mutation is 1226 C
We know of no formal studies that compare the severity of Gaucher
disease among persons in the general population, siblings, and
monozygotic twins. Because the extended haplotype (linked polymorphic
markers) of the common mutation 1226A What could such environmental factors be? One factor that deserves
attention is early experience with infections such as
infectious mononucleosis. We know of 3 patients in whom relatively
severe disease developed, diagnosed after the development of infectious mononucleosis, and Kolodny et al40 earlier called
attention to this association. Suppose, for example, that a child with
Gaucher disease is infected with the Epstein-Barr virus. This results in splenomegaly and increased sequestration of leukocyte-derived glycolipid in the spleen. When the virus infection has been controlled, the spleen may remain in an enlarged state and, as such, sequester leukocytes and their lipids at an accelerated rate. Perhaps a vicious
circle ensues, consisting of increased splenic sequestration, progressive splenomegaly, and a further increase in the rate of sequestration. I have, in fact, seen a patient whose diagnosis was
established after a bout of infectious mononucleosis, and this
patient's disease was much more aggressive than that of her brother
with the same 1226G/1226G genotype. This phenomenon could be
investigated by studying antibody levels in patients with Gaucher disease with different degrees of clinical manifestations. Another possible environmental factor is the diet. Indeed, on learning that
they have lipid storage disease, most patients with Gaucher disease
ask, "Should I change my diet?" The source of the glycolipid is, of
course, endogenous; hence, the standard answer is, "No, this fatty
substance does not arise from foods you ingest." Nonetheless, I know
of no studies that have explored the effect of dietary intake on the
rate of glycolipid accumulation.
No serious candidate genes that might explain phenotypic
variability of Gaucher disease have emerged. It is notable that in addition to the acid Only recently has the enormous variability of the clinical
manifestations of hereditary hemochromatosis been appreciated. As
described in the classical 1935 monograph written by
Sheldon,43 a patient with hemochromatosis had cirrhosis,
diabetes, bronzing of the skin, and cardiac arrhythmias. With the
advent of population screening through serum transferrin saturation and
serum ferritin levels and the study of family members, particularly by
examining linkage with HLA-A, it became apparent that there were many
patients thought to have hemochromatosis who lacked many or most
clinical manifestations of the disease. However, it was not until
cloning of the HFE gene Although most Europeans with hereditary hemochromatosis are
homozygous for the C282Y mutation of the HFE gene, the
reverse is clearly not true. There is general agreement that many
patients with the homozygous genotype do not have clinical
hemochromatosis. Some studies suggest that 50% or more of homozygotes
have some degree of cirrhosis.44,45 It may be significant
that some of these studies were performed on relatives of patients who
had the clinical disorder44; clearly, they would be more
likely to carry the very modifying genes required for hemochromatosis to become manifest. Our own experience, based on a population of
patients attending a health appraisal clinic, is that penetrance of the
hemochromatosis mutations is extremely low. Only one of the
first 152 homozygotes we detected had clinical hemochromatosis, and the prevalence of symptoms such as arthritis, impotence, and diabetes, thought to be common in hemochromatosis, were no more common
in controls than in homozygotes for the C282Y mutation.46 The studies of Willis et al47-49 support the view that the
penetrance of the gene is very low. These data suggest to us that
homozygosity for the C282Y mutation of HFE is a
necessary, but not a sufficient, condition for the full-blown clinical
disorder to develop.
What, then, could the other accessory factors be? An obvious
consideration is the dietary intake of iron. There are two reasons why
this seems unlikely. First, the normal range of iron intake is
relatively narrow, yet the range of iron storage in patients with the
hemochromatosis genotype is enormous. Second, studies of the effect of
iron supplementation of the diet on the incidence of hemochromatosis
showed no increase in the incidence of disease during the years the
diet was supplemented with iron.50 It seems more likely
that other genes might determine whether clinical hemochromatosis
develops. Mutation of such genes might, on the one hand, be
responsible for hemochromatosis in patients who do not have
HFE mutations. On the other hand, they could influence the
severity of the hemochromatosis phenotype in those patients who are
homozygous for the C282Y mutation or who are homozygotes for the H63D
mutation. Table 2 represents a list of
candidate genes that either are being investigated or have been
studied. If one or more of these prove to have polymorphisms that
increase iron absorption, then the coinheritance of such mutations with the HFE mutations may be what is required to give rise to
classical hemochromatosis, a situation analogous with the UDP
glucuronosyltransferase mutation that produces Gilbert disease and
interacts with G6PD deficiency to cause jaundice.
Most disorders of hemostasis are genetically heterogeneous.
Therefore, a considerable amount of the notorious variability observed
in these disorders can be accounted for by differences in the mutation
the patient carries. Even within families, however, there is marked
variability in the amount of bleeding in patients with the more common
disorders such as hemophilia A, hemophilia B, or von Willebrand
disease. The most common of the genetic defects is the factor V Leiden
mutation (c.1691 G
The five examples discussed here are typical of the wide range of phenotypic manifestations of so-called single-gene diseases. None of the problems they pose are fully resolved, and in most cases we have only a few clues as to the nature of the interactions required to produce the severe and mild extremes of phenotypes with which we are familiar. Understanding the cause of phenotypic variation in patients with the same genotype is critical for genetic counseling and for management. Only when we can predict more accurately the natural course for a patient can we make valid risk-benefit and cost-benefit assessments for treatment. If we knew that a given patient with sickle disease had a high probability for stroke, we would more readily subject that patient to the risk of stem cell transplantation. If we could predict that a patient with Gaucher disease would have severe bone involvement, the expenditure of $200 000 per year for enzyme replacement therapy could be better justified. Moreover, if we understood why some patients have mild disease, this knowledge might lead to treatments that create the same conditions in patients with severe disease. In approaching this problem, it is important, first of all, to have
some understanding of the relative contributions of heredity and
environment in causing phenotypic variation. This information is best
obtained from monozygotic twins, but it is generally unavailable. A
coordinated effort to find and evaluate such twin sets should be made.
If there is as much variability in monozygotic twins as in the general
population, a search for a genetic cause of variability would surely be
futile. When there is reason to believe that genetic factors are
responsible, 2 general approaches may be taken There is great enthusiasm for moving on to find the causes of multigenic diseases such as diabetes and rheumatoid arthritis. I would submit that it will be even more difficult to understand these disorders than the single-gene diseases, the causes of whose variability still elude us.
This is manuscript number 13400-MEM from The Scripps Research Institute.
Submitted May 15, 2001; accepted July 3, 2001.
Supported by National Institutes of Health grants HL25552-10, DK53505-02, and RR00833 and by the Stein Endowment Fund.
@ 2001 by The American Society of Hematology
Reprints: Ernest Beutler, Department of Molecular and Experimental Medicine, MEM-215, The Scripps Research Institute, 10550 N Torrey Pines Rd, La Jolla, CA 92037; e-mail: beutler{at}scripps.edu.
1. Serjeant G, Serjeant B, Stephens A, et al. Determinants of haemoglobin level in steady-state homozygous sickle cell disease. Br J Haematol 1996;92:143-149[CrossRef][Medline] [Order article via Infotrieve]. 2. Beutler E. The effect of methemoglobin formation in sickle cell disease. J Clin Invest. 1961;40:1856-1871.
3.
Powars DR, Weiss JN, Chan LS, Schroeder WA.
Is there a threshold level of fetal hemoglobin that ameliorates morbidity in sickle cell anemia?
Blood.
1984;63:921-926 4. El-Hazmi MAF, Al-Swailem AR, Bahakim HM, Al-Faleh FZ, Warsy AS. Effect of alpha thalassaemia, G-6-PD deficiency and Hb F on the nature of sickle cell anaemia in south-western Saudi Arabia. Trop Geogr Med. 1990;42:241-247[Medline] [Order article via Infotrieve]. 5. Green NS, Fabry ME, Kaptue-Noche L, Nagel RL. Senegal haplotype is associated with higher HbF than Benin and Cameroon haplotypes in African children with sickle cell anemia. Am J Hematol. 1993;44:145-146[Medline] [Order article via Infotrieve]. 6. Steinberg MH. Sickle cell anemia and fetal hemoglobin. Am J Med Sci. 1994;308:259-265[Medline] [Order article via Infotrieve].
7.
Platt OS, Thorington BD, Brambilla DJ, et al.
Pain in sickle cell disease 8. Thein SL, Craig JE. Genetics of Hb F/F cell variance in adults and heterocellular hereditary persistence of fetal hemoglobin. Hemoglobin. 1998;22:401-414[Medline] [Order article via Infotrieve].
9.
Beutler E, Paniker NV, West C.
The effect of 2,3-DPG on the sickling phenomenon.
Blood.
1971;37:184-186
10.
Beutler E.
Hypothesis: changes in the 02 dissociation curve and sickling: a general formulation and therapeutic strategy.
Blood.
1974;43:297-300
11.
Poillon WN, Kim BC.
2,3-Diphosphoglycerate and intracellular pH as interdependent determinants of the physiologic solubility of deoxyhemoglobin S.
Blood.
1990;76:1028-1036 12. Charache S, Grisolia S, Fiedler AJ, Hellegers AE. Effect of 2,3-diphosphoglycerate on oxygen affinity of blood in sickle cell anemia. J Clin Invest. 1970;49:806-812.
13.
Cohen-Solal M, Préhu C, Wajcman H, et al.
A new sickle cell disease phenotype associating Hb S trait, severe pyruvate kinase deficiency (PK Conakry), and an 14. Embury SH, Dozy AM, Miller J, et al. Concurrent sickle-cell anemia and alpha-thalassemia: effect on severity of anemia. N Engl J Med. 1982;306:270-274[Abstract]. 15. Nagel RL, Ranney HM. Genetic epidemiology of structural mutations of the beta-globin gene. Semin Hematol. 1990;27:342-359[Medline] [Order article via Infotrieve].
16.
Beutler E.
G6PD deficiency.
Blood.
1994;84:3613-3636 17. Ohno S, Kaplan WD, Kinosita R. On isopycnotic behavior of the XX-bivalent in oocytes of Rattus norvegicus. Exp Cell Res. 1960;19:637-639.
18.
Beutler E, Yeh M, Fairbanks VF.
The normal human female as a mosaic of X-chromosome activity: studies using the gene for G-6-PD deficiency as a marker.
Proc Natl Acad Sci U S A.
1962;48:9-16 19. Lyon MF. Gene action in the X-chromosome of the mouse (Mus musculus l). Nature. 1961;190:372-373[CrossRef][Medline] [Order article via Infotrieve]. 20. Willard HF. X chromosome inactivation, XIST, and pursuit of the X-inactivation center. Cell. 1996;86:5-7[CrossRef][Medline] [Order article via Infotrieve]. 21. Dern RJ, Beutler E, Alving AS. The hemolytic effect of primaquine, V: primaquine sensitivity as a manifestation of a multiple drug sensitivity. J Lab Clin Med. 1955;45:30-39. 22. Magon AM, Leipzig RM, Zannoni VG, Brewer GJ. Interactions of glucose-6-phosphate dehydrogenase deficiency with drug acetylation and hydroxylation reactions. J Lab Clin Med. 1981;97:764-770[Medline] [Order article via Infotrieve]. 23. Stamatoyannopoulos G, Fraser GR, Motulsky AG, Fessas P, Akrivakis A, Papayannopoulou T. On the familial predisposition to favism. Am J Hum Genet. 1966;18:253-263[Medline] [Order article via Infotrieve].
24.
Bottini E, Lucarelli P, Agostino R, Palmarino R, Bosinco L, Antognoni G.
Favism: association with erythrocyte acid phosphatase phenotype.
Science.
1971;171:409-411 25. Cassimos CHR, Malaka-Zafiriu K, Tsiures J. Urinary d-glucaric acid excretion in normal and G-6-PD-deficient children with favism. J Pediatr. 1974;84:871-872[CrossRef][Medline] [Order article via Infotrieve]. 26. Cutillo S, Costa S, Vintuleddu MC, Meloni T. Salicylamide-glucuronide formation in children with favism and in their parents. Acta Haematol (Basel). 1976;55:296-299. 27. Mavelli I, Ciriolo MR, Rossi L, et al. Favism: a hemolytic disease associated with increased superoxide dismutase and decreased glutathione peroxidase activities in red blood cells. Eur J Biochem. 1984;139:13-18[Medline] [Order article via Infotrieve]. 28. Monaghan G, Ryan M, Seddon R, Hume R, Burchell B. Genetic variation in bilirubin UDP-glucuronosyltransferase gene promotor and Gilbert's syndrome. Lancet. 1996;347:578-581[CrossRef][Medline] [Order article via Infotrieve].
29.
Kaplan M, Renbaum P, Levy-Lahad E, Hammerman C, Lahad A, Beutler E.
Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: a dose-dependent genetic interaction crucial to neonatal hyperbilirubinemia.
Proc Natl Acad Sci U S A.
1997;94:12128-12132 30. Galanello R, Cipollina MD, Carboni G, et al. Hyperbilirubinemia, glucose-6-phosphate-dehydrogenase deficiency and Gilbert's syndrome. Eur J Pediatr. 1999;158:914-916[CrossRef][Medline] [Order article via Infotrieve]. 31. Perrotta S, Del Giudice EM, Carbone R, et al. Gilbert's syndrome accounts for the phenotypic variability of congenital dyserythropoietic anemia type II (CDA-II). J Pediatr. 2000;136:556-559[CrossRef][Medline] [Order article via Infotrieve].
32.
Iolascon A, Faienza MF, Moretti A, Perrotta S, Del Giudice EM.
UGT1 promoter polymorphism accounts for increased neonatal appearance of hereditary spherocytosis.
Blood.
1998;91:1093-1094
33.
Del Giudice EM, Perrotta S, Nobili B, Specchia C, d'Urzo G, Iolascon A.
Coinheritance of Gilbert syndrome increases the risk for developing gallstones in patients with hereditary spherocytosis.
Blood.
1999;94:2259-2262 34. Iolascon A, Faienza MF, Giordani L, et al. Bilirubin levels in the acute hemolytic crisis of G6PD deficiency are related to Gilbert's syndrome. Eur J Haematol. 1999;62:307-310[Medline] [Order article via Infotrieve].
35.
Daneman A, Stringer D, Reilly BJ.
Neonatal ascites due to lysosomal storage disease.
Radiology.
1983;149:463-467 36. Ginsburg SJ, Groll M. Hydrops fetalis due to infantile Gaucher's disease. J Pediatr. 1973;82:1046-1048[CrossRef][Medline] [Order article via Infotrieve]. 37. Sun CC, Panny S, Combs J, Gutberlett R. Hydrops fetalis associated with Gaucher disease. Pathol Res Pract. 1984;179:101-104[Medline] [Order article via Infotrieve]. 38. Berrebi A, Wishnitzer R, Von der Walde U. Gauchers disease: unexpected diagnosis in three patients over seventy years old. Nouv Rev Fr Hematol. 1984;26:201-203. 39. Chang-Lo M, Yam LT. Gaucher's disease: review of the literature and report of twelve new cases. Am J Med Sci. 1967;254:303-315[Medline] [Order article via Infotrieve]. 40. Kolodny EH, Ullman MD, Mankin HJ, Raghavan SS, Topol J, Sullivan JL. Phenotypic manifestations of Gaucher disease: clinical features in 48 biochemically verified type I patients and comment on type II patients. In: Desnick RJ,Gatt S,Grabowski GA, eds. Gaucher Disease: A Century of Delineation and Research. New York, NY: Alan R. Liss, Inc; 1982:33-65. 41. Aerts JMFG, Donker-Koopman WE, van Laar C, et al. Relationship between the two immunologically distinguishable forms of glucocerebrosidase in tissue extracts. Eur J Biochem. 1987;163:583-589[Medline] [Order article via Infotrieve]. 42. van Weely S, Van den Berg M, Barranger JA, Sa Miranda MC, Tager JM, Aerts JMFG. Role of pH in determining the cell type-specific residual activity of glucocerebrosidase in type 1 Gaucher disease. J Clin Invest. 1993;91:1167-1175. 43. Sheldon JH. Haemochromatosis. London, England: Oxford University Press; 1935. 44. Bulaj ZJ, Edwards CQ, Ajioka RS, Phillips JD, Kushner JP. Frequency of disease-related morbidity in 214 clinically unselected hemochromatosis homozygotes [abstract]. Blood. 1999;94(suppl 1):644.
45.
Olynyk JK, Cullen DJ, Aquilia S, Rossi E, Summerville L, Powell LW.
A population-based study of the clinical expression of the hemochromatosis gene.
N Engl J Med.
1999;341:718-724 46. Beutler E, Felitti VJ, Koziol JA, Ho N, Gelbart T. Penetrance of the 845G6A (C282Y) HFE hereditary hemochromatosis mutation. Lancet. In press.
47.
Willis G, Fellows IW, Wimperis JZ.
Deaths attributed to haemochromatosis are rare in Britain [abstract].
BMJ.
2000;320:1146
48.
Willis G, Wimperis JZ, Lonsdale R, et al.
Incidence of liver disease in people with HFE mutations.
Gut.
2000;46:401-404 49. Willis G, Wimperis JZ, Smith KC, Fellows IW, Jennings BA. Haemochromatosis gene C282Y homozygotes in an elderly male population. Lancet. 1999;354:221-222[CrossRef][Medline] [Order article via Infotrieve]. 50. Olsson KS, Säfwenberg J, Ritter B. The effect of iron fortification of the diet on clinical iron overload in the general population. Ann N Y Acad Sci. 1988;526:290-300[Abstract].
51.
Bahram S, Gilfillan S, Kuhn LC, et al.
Experimental hemochromatosis due to MHC class I HFE deficiency: immune status and iron metabolism.
Proc Natl Acad Sci U S A.
1999;96:13312-13317 52. Levy JE, Montross LK, Andrews NC. Genes that modify the hemochromatosis phenotype in mice. J Clin Invest. 2000;105:1209-1216[Medline] [Order article via Infotrieve]. 53. Feder JN, Gnirke A, Thomas W, et al. A novel MHC class I-like gene is mutated in patients with hereditary haemochromatosis. Nat Genet. 1996;13:399-408[CrossRef][Medline] [Order article via Infotrieve]. 54. Beutler E, West C. New diallelic markers in the HLA region of chromosome 6. Blood Cells Mol Dis. 1997;23:219-229[CrossRef][Medline] [Order article via Infotrieve]. 55. de Sousa M, Reimao R, Lacerda R, Hugo P, Kaufmann SH, Porto G. Iron overload in beta 2-microglobulin-deficient mice. Immunol Lett. 1994;39:105-111[CrossRef][Medline] [Order article via Infotrieve]. 56. Levy JE, Jin O, Fujiwara Y, Kuo F, Andrews NC. Transferrin receptor is necessary for development of erythrocytes and the nervous system. Nat Genet. 1999;21:396-399[CrossRef][Medline] [Order article via Infotrieve]. 57. Tsuchihashi Z, Hansen SL, Quintana L, et al. Transferrin receptor mutation analysis in hereditary hemochromatosis patients. Blood Cells Mol Dis. 1998;24:317-321[CrossRef][Medline] [Order article via Infotrieve]. 58. Camaschella C, Roetto A, Cali A, et al. The gene TFR2 is mutated in a new type of haemochromatosis mapping to 7q22. Nat Genet. 2000;25:14-15[CrossRef][Medline] [Order article via Infotrieve]. 59. Lee PL, Halloran C, West C, Beutler E. Mutation analysis of the transferrin receptor-2 gene in patients with iron overload. Blood Cells Mol Dis. 2001;27:285-289[CrossRef][Medline] [Order article via Infotrieve]. 60. Aguilar-Martinez P, Esculie-Coste C, Bismuth M, Giansily-Blaizot M, Larrey D, Schved JF. Transferrin receptor-2 gene and non-C282Y homozygous patients with hemochromatosis. Blood Cells Mol Dis. 2001;27:290-293[CrossRef][Medline] [Order article via Infotrieve]. 61. Barton EH, West PA, Rivers CA, Barton JC, Acton RG. Transferrin receptor-2 (TFR2) mutation Y250X in Alabama Caucasian and African American subjects with and without primary iron overload. Blood Cells Mol Dis. 2001;27:279-284[CrossRef][Medline] [Order article via Infotrieve]. 62. Hamill RL, Woods JC, Cook BA. Congenital atransferrinemia: a case report and review of the literature. Am J Clin Pathol. 1991;96:215-218[Medline] [Order article via Infotrieve].
63.
Raja KB, Pountney DJ, Simpson RJ, Peters TJ.
Importance of anemia and transferrin levels in the regulation of intestinal iron absorption in hypotransferrinemic mice.
Blood.
1999;94:3185-3192 64. Lee PL, Ho NJ, Olson R, Beutler E. The effect of transferrin polymorphisms on iron metabolism. Blood Cells Mol Dis. 1999;25:374-379[CrossRef][Medline] [Order article via Infotrieve]. 65. Dennery PA, Spitz DR, Yang G, et al. Oxygen toxicity and iron accumulation in the lungs of mice lacking heme oxygenase-2. J Clin Invest. 1998;101:1001-1011[Medline] [Order article via Infotrieve]. 66. Okamoto N, Wada S, Oga T, et al. Hereditary ceruloplasmin deficiency with hemosiderosis. Hum Genet. 1996;97:755-758[Medline] [Order article via Infotrieve]. 67. Lee PL, Gelbart T, West C, Halloran C, MacDonald M, Beutler E. A study of genes that may modulate the expression of hereditary hemochromatosis: transferrin receptor-1, ferritin heavy and light chains, ferroportin, ceruloplasmin, iron responsive binding proteins (IRP)-1 and -2. Blood Cells Mol Dis. In press. 68. Fleming MD, Trenor CC, Su MA, et al. Microcytic anaemia mice have a mutation in Nramp2, a candidate iron transporter gene. Nat Genet. 1997;16:383-386[CrossRef][Medline] [Order article via Infotrieve].
69.
Fleming MD, Romano MA, Su MA, Garrick LM, Garrick MD, Andrews NC.
Nramp2 is mutated in the anemic belgrade (b) rat: evidence of a role for nramp2 in endosomal iron transport.
Proc Natl Acad Sci U S A.
1998;95:1148-1153 70. Lee PL, Gelbart T, West C, Halloran C, Beutler E. The human nramp2 gene: characterization of the gene structure, alternative splicing, promoter region and polymorphisms. Blood Cells Mol Dis. 1998;24:199-215[CrossRef][Medline] [Order article via Infotrieve]. |
Top
Abstract
General considerations
-thalassemic mutations. Because the latter mutations are themselves heterogenous, it
is only the S-S and the S-C forms of sickle cell disease that are
homogeneous. Within each of these groups there is a great deal of
clinical heterogeneity.
-thalassemia and the severity of
sickling has been known for nearly 20 years.
the responses of different patients
with the same mutation to a single drug dose may vary
widely,
G
(N270S), and though all patients carrying this mutation have the type
1, nonneuropathic form of the disease, the phenotype of patients varies
widely. As shown in Figure 