Cytogenetic, Clinical, Biochemical and Pharmacological Aspects of Glucose 6 Phosphate Dehydrogenase - An Updated Review
Amar
Nagesh Kumar1*, Sunil M. Vishwasrao2
1Department of Biochemistry, Karpaga Vinayaga
Institute of Medical Sciences and Research Center, Chinakolambakkam,
Madhurantagam, Tamil Nadu, India
2Department of Pharmacology, Karpaga Vinayaga
Institute of Medical Sciences and Research Center, Chinakolambakkam,
Madhurantagam, Tamil Nadu, India
*Corresponding author: Amar Nagesh Kumar,
Department of Biochemistry, Karpaga Vinayaga Institute of Medical Sciences and
Research Center, Chinakolambakkam, Madhurantagam, Tamil Nadu, India. Tel:
+91-9944462915; Email: amarnageshkumar@gmail.com
Received Date: 01 January, 2019; Accepted Date: 11 March, 2019; Published Date: 19 March, 2019
Citation: Kumar AN, Vishwasrao SM (2019) Cytogenetic, Clinical,
Biochemical and Pharmacological Aspects of Glucose 6 Phosphate Dehydrogenase -
An Updated Review. Adv Biochem Biotechnol 7: ABIO-082. DOI:
10.29011/2574-7258.000082
Abstract
Glucose 6 Phosphate Dehydrogenase (G6PD) is
one of the rate-limiting enzymes in hexose monophosphate pathway. G6PD
deficiency is an X-linked inheritable abnormality in humans and mostly males
are affected, while females are carriers only. The cytogenetic location for all
mutations that cause G6PD deficiency is on the band Xq28 of the long arm of the
X chromosome, and the locus of the G6PD gene is at Xq27.3 chromosomes.
Mutations in the G6PD gene may reduce the amount of G6PD or alter its
structure. Most individuals with G6PD deficiency have a qualitative
abnormality in the structure of the G6PD enzyme. The deficiency is more
commonly found in persons of African, Mediterranean, South Asian, and
Middle-Eastern countries. G6PD deficiency is seen to occur most frequently
in the areas where malaria is common. G6PD deficiency can cause a spectrum
of symptoms that include hemolytic anemia caused by ingestion or exposure to
certain triggers. Anemia in turn causes jaundice, pale skin or finger nails,
lethargy, fatigue, shortness of breath and fever, among others. The
diagnosis of heterozygous deficient women is especially complicated because
these women have a normal and a G6PD-deficient population of erythrocytes as a
result of lyonization. In this context, knowledge of G6PD enzyme and its
deficiency is very essential for clinicians and researchers. Hence an attempt
has been made in this article to summarize the cytogenetic, clinical,
biochemical and pharmacological aspects of G6PD enzyme.
Keywords: Enzymopathy; Favism;
Glucose 6 Phosphate; Lyonization; Malaria; X-linked inheritance
Glucose 6 Phosphate
Dehydrogenase (G6PD) is one of the rate-limiting enzymes in Hexose
Monophosphate Pathway (HMP Pathway) and plays an important role in Red Blood
Cells (RBC). Deficiency of G6PD is an X-linked inheritable abnormality in
humans. The role of G6PD, advantages of its deficiency has been of interest to
researchers and clinicians since its discovery by Dr Ernest Beutler in 1953, and
first reported by Alving, et al. in 1956 while investigating the unusual
hemolytic reaction that occurred in ethnic black individuals following the
administration of primaquine for the treatment of malaria [1,2]. Symptomatic
patients are almost all male persons, due to the X-linked pattern of
inheritance. Females are carriers can clinically have affected due to unfavorable
lyonization. G6PD deficiency is also known as favism.
Classification
According to the World
Health Organization (WHO) G6PD genetic variants classified into five classes
[3]. These include:
· Severe deficiency (<10% activity) with
chronic (nonspherocytic) hemolytic anemia
· Severe deficiency (<10% activity) with
intermittent hemolysis
· Mild deficiency (10-60% activity) and hemolysis
seen with stressors only
· Non-deficient variant with no clinical sequel
· Increased enzyme activity with no clinical
sequel
· Different gene mutations cause different levels
of enzyme deficiency, with classes assigned to various degrees of deficiency
and disease manifestation as shown in Table 1 [4,5].
Cytogenetics and
Molecular Aspects of G6PD
More than 140 mutations
that cause G6PD deficiency have been identified in the G6PD gene. The
cytogenetic location for all mutations that cause G6PD deficiency is on the
band Xq28 of the long arm of the X chromosome, and the locus of the G6PD
gene is at Xq27.3 chromosomes [4,5]. The molecular location on the X chromosome
is base pairs 153,759,605 to 153,775,786. The molecular data on human G6PD
shows that for DNA, the size of gene is 18.5 kilobases and the number of exons
and introns are 13 and 12 respectively [4,5]. Size in nucleotides is 2269 for
mRNA, and the protein has 515 amino acids [4,5]. G6PD, in its active
enzyme form, is made up of either two or four identical subunits, each having a
molecular mass of 59,265 kilo-Daltons; this is more than three times that of
the hemoglobin molecule [6].
Mutations in the G6PD
gene may reduce the amount of G6PD or alter its structure. Most
individuals with G6PD deficiency have a qualitative abnormality in the
structure of the G6PD enzyme. Many models have been proposed suggesting
possible reasons why an abnormal enzyme is not fully active. One of the
suggestions is that the decreased stability of a mutated enzyme results either
from a change in the conformation of the G6PD molecule or from an increase in
its susceptibility to proteolytic enzymes. In either case, the G6PD enzyme is
not fully active when it is mutated [6,7]. Wang et al reported the first
case of a G6PD-deficient Chinese patient in the category of class I (WHO
classification) in the Liaoning Province in northeastern China in 2010 [8,9].
The patient was a 3-year-old boy in whom the G6PD gene had a replacement of G
to A at nucleotide 1339. As a result, the amino acid at position 447 should
change from Gly to Arg. This replacement is known as G6PD Santiago de Cuba,
because it was first discovered in a Cuban boy who showed heavy chronic anemia.
Until this report, 28 G6PD variants had been reported in the Chinese
population, all of which were in the class II (severe deficiency) or class III
(mild deficiency). No case of G6PD deficiency was reported in 414 blood samples
from northeastern China. In central China, where falciparum malaria was endemic
from the 1950s to 1970s, 2 cases of G6PD deficiency were found amongst 27 blood
samples. These cases and the other members from their families had variant type
G6PD Kaiping (1388G > T), which is a common variant in the Chinese
population [9].
G6PD deficiency is
inherited from one or both the parents. It cannot be passed from one person to
another in any other way (non-communicable disease). Males can either be G6PD
deficient or unaffected. Females can be unaffected or carriers or affected. Probability
of inheritance with each pregnancy is summarized in Table 2 [10-13]. The
inheritance pattern based on the X-linked recessive nature of the illness is
shown in Punnett charts in Tables 3-5.
Clinical Aspects of G6PD
Prevalence
Glucose 6-phosphate
dehydrogenase is the most common human enzyme defect being present in more than
400 million people worldwide [14,6]. The deficiency is more commonly found in
persons of African, Mediterranean, South Asian, and Middle-Eastern countries
[15]. G6PD deficiency is also prevalent in Sardinia, Italy. WHO data from 1989
reported the prevalence of 0.39% in Europe, which represents in France 120,000
deficient male patients and approximately 1,400 new cases among male newborn
babies. From technologically deficient areas in the world, the reporting of the
G6PD deficiency may be inadequate. While Philippines had few or no cases of
G6PD deficiency earlier, now that newborn screening has been implemented, 12%
of its population is reported to be affected. A report in 2000
mentioned an estimated 225,000 males and 92,000 females were affected in Greece
[16]. Reportedly, 1 in 10 African-American males in United States
is affected by this condition. It may be seen in about 20% population in
Africa, 4-30% in Mediterranean, and in Southeast Asians. A study from Solomon
Islands in 8541 individuals (3880 males and 4636 females), found 20.3% overall
prevalence (21.7% in males and 19.1% in females) of G6PD deficiency and 6.9%
prevalence of severe deficiency (less than 10% of normal enzyme activity) [17].
Cases of sporadic gene mutation may occur in all populations.
The two most common
variants of G6PD deficiency are G6PD Mediterranean and G6PD-A variant. G6PD
Mediterranean variant falls in WHO Class II and mainly affects Italian,
Grecian, Spanish, and the individuals from middle eastern descent such as
Arabic, Kurdish or Sephardic Jewish populations. In this variant, the neonatal
hyperbilirubinemia is known to occur and may be more severe, and favism is more
common [18-21]. The G6PD-A variant falls in WHO Class III and mainly affects
the population of African descent. Neonatal hyperbilirubinemia may be seen in
this variant also, and favism is less common. Hemolysis on exposure to
oxidative stress is seen in both these variants [17,22-24].
Clinical Features of
G6PD Deficiency
So far more than 440
different variants of enzyme G6PD have been identified with level of deficiency
ranging from severe to mild. Of which around 80 G6PD variants are associated
with chronic non-spherocytic hemolytic anemia [7,15,18]. Most individuals with
G6PD deficiency are asymptomatic (can be homozygous or heterozygous) [18-20].
G6PD deficiency can cause a spectrum of symptoms that include hemolytic anemia
caused by ingestion or exposure to certain triggers. Anemia in turn causes
jaundice, pale skin or finger nails, lethargy, fatigue, shortness of breath and
fever, among others. These symptoms usually go away on their own when exposure
to the trigger is removed [16,19-20]. In newborns, G6PD deficiency may
cause persistent jaundice. If left untreated, this may lead to brain damage
(kernicterus) and mental retardation [8]. Individuals with the disease may
exhibit non-immune hemolytic anemia in response to a number of causes, most
commonly exposure to certain medications (antimalarial or antihistamine/anti
pyritic drugs or chemicals or bacterial or viral infections [21-24].
Biochemistry of G6PD
The enzyme
Glucose-6-Phosphate Dehydrogenase (G6PD) is a dimer and tetramer, taking part
in the step in the Hexose-Monophosphate (HMP) pathway. G6PD has 400 isoforms
[8,16-17]. Among all, the G6PD in RBC is 351±60.6 U/1012 RBC [8,14]. It is an NADP dependent enzyme and is involved in
maintenance of RBC membrane integrity. Due to the presence of oxygen, hydrogen
peroxide is continuously formed inside the RBCs. Hydrogen peroxide destroys bio
membranes and therefore there is lysis of RBCs. This is prevented by a process
involving glutathione and NADPH. The biochemical reaction involving G6PD is
shown in Figure 1. In the G6PD deficient individuals, the normal in
vivo life half-life of RBCs of 62 days’ decreases to as less as 13 days, resulting
in mild hemolysis and is aggravated by exposure to certain drugs such as
primaquine [10].
Role of G6PD in Various
Functions
Embryo Protective Role
of G6PD
Glucose-6-phosphate
dehydrogenase is known to be cytoprotective against oxidative stress especially
to the red blood cells. Nicol et al showed that litters from untreated pregnant
mutant mice with a hereditary G6PD deficiency had increased prenatal (fetal resorptions)
and postnatal death. When treated with the anticonvulsant drug phenytoin,
G6PD-deficient dams had higher embryonic DNA oxidation and more fetal death and
birth defects. The reported G6PD gene mutation was confirmed and used to
genotype fetal resorptions, which were primarily G6PD deficient. This study was
claimed to be the first evidence that G6PD is a developmentally critical
cytoprotective enzyme for both endogenous and xenobiotic-initiated embryo
pathic oxidative stress and DNA damage, and suggested that G6PD deficiencies
accordingly may have a broader biological relevance as important determinant of
infertility, in utero and postnatal death, and teratogenesis [18].
G6PD Deficiency as an
Advantage
Deficiency of
glucose-6-phosphate dehydrogenase enzyme is thought to pose advantages in
certain situations. Suggested situations include malaria, retinal vein
occlusion, and ischemic heart and cerebrovascular disease [19].
G6PD deficiency and
retinal vein occlusion. A study from Sardinia (Italy) showed that the patients
deficient in G6PD were found to have a significantly lower risk of developing
Retinal Vein Occlusion (RVO) [19].
G6PD Deficiency and
Malaria
G6PD deficiency is seen
to occur most frequently in the areas where malaria is common. The researchers
believe that the carriers of a G6PD mutation may be partially protected against
malaria. The fact that the prevalence of G6PD deficiency correlates with
endemicity for malaria had led to the hypotheses that G6PD deficiency may be
result of natural selection conferring protection against malaria infection [20-23]. However, studies have indicated that this
protection may only occurs with certain G6PD variants, and that differing level
of protection are likely to be seen in hemizygous males, homozygous and
heterozygous females [24].
The incidence of the
most common form of glucose 6-phosphate dehydrogenase deficiency, characterized
by a tenfold reduction in enzymatic activity in red blood cells, is 11% among
Americans of African heritage. This high frequency suggests that the deficiency
may be advantageous under certain environmental conditions. Indeed, glucose
6-phosphate dehydrogenase deficiency protects against falciparum malaria
[25-27]. The parasites causing this disease to require reduced glutathione and
the products of the pentose phosphate pathway for optimal growth. Thus, glucose
6-phosphate dehydrogenase deficiency is a mechanism of protection against
malaria, which accounts for its high frequency in malaria-infested regions of
the world [28]. So also, a reduction in the amount of functional G6PD
appears to make it more difficult for the malarial parasite to invade red blood
cells. Another theory says that the cells infected with the Plasmodium parasite
are cleared more rapidly by the spleen. This phenomenon might give G6PDH
deficiency carriers an evolutionary advantage by increasing their fitness in
malarial endemic environments. Because hemolysis affects mature red blood cells
more readily, there are fewer of them to host malaria parasites. When an
infected RBC dies before the parasite is ready, the malaria parasite dies as
well and it does not have the chance to produce the poisons. Because of this
the typical symptoms do not usually manifest themselves in G6PD deficient
patients. Atypical symptoms could make malaria more difficult to diagnose and
account for the belief that it is less prevalent in G6PD Deficient patients.
Malaria can still sequester in the liver however. The dangerous part is that a
person can die or become very ill from hemolysis and G6PD deficiency patients
cannot take antimalarial. All of the antimalarial listed by the CDC are
contraindicated except Doxycycline, which cannot be taken by pregnant women or
children under the age of eight. People must limit their sun exposure while on
the drug as well [4,14,26].
Hemolysis in G6PD
Deficiency Can Manifest in Many Ways
Acute hemolysis is
caused by exposure to an oxidative stress or in the form of an infection,
oxidative drugs or fava beans. Acute hemolysis, which is self-limiting, may be
rarely severe enough to warrant blood transfusion. Neonatal hyperbilirubinemia
may require phototherapy or exchange transfusion to prevent kernicterus. The
variant causing chronic hemolysis is uncommon because it is related to sporadic
/9gene mutation rather than the more common inherited gene mutation [15].
They include
· Prolonged neonatal jaundice in turn may lead to
kernicterus, the most serious complication of G6PD deficiency.
· Hemolytic anemia in response to
· Unusual complication of infections
· Certain drugs
· Certain foods (favabeans)
· Chemicals
· Diabetic ketoaciodosis
Important Drugs Cause
Hemolysis Due to G6D Deficiency
Many drugs are
potentially harmful to people with G6PD deficiency, and they produce oxidative
damage to erythrocytes leading erythrocyte destruction [22-24]. Hemolysis is
typically known to occur 24-72 hours after ingestion and resolves within 5-7
days [23]. Oxidative drugs are known to cross the milk barrier and produce
oxidative damage and hemolysis in the breast-fed infant [25]. Some of the drugs
which can cause hemolysis in G6PD deficient subjects are listed below.
· Antimalarials: Primaquin, Pamaquin and chloroquin
· Analgesics: Acetyl salicylic acid, Phenacetin, Phenazopyridine,
Acetanilide
· Sulphonamides: Sulphanilamide, Sulphamethazole and Mafenide
· Sulphones: Thiazole sulphone, Dapsone, Sulphoxone
· Nitrofurans: Furadantin, Furoxone [23-25,27,28]
Fava beans ingestion has
been identified to precipitate the symptoms of G6PD deficiency in some G6PD
deficient individuals, although all individuals may not exhibit hemolysis upon
fava beans ingestion [1,4,11,20]. Favism is most common in individuals with G6PD
class II variants, but rarely occurs in individuals with G6PD A-variant.
Although the exact ingredient in fava beans responsible for oxidative damage is
unknown, it could be possibly vicine, convicine, or isouramil. Fava
beans are also known as Bell beans or Horse beans. Bell beans are known by
various names that include broad beans, English dwarf beans, fever beans or
haba beans. Horse beans are known by different names including pigeon beans,
silk worm beans or tick beans [29-31].
Diagnostics - Testing
Methods
The diagnosis of
heterozygous deficient women is especially complicated because these women have
a normal and a G6PD-deficient population of erythrocytes as a result of
lyonization. Hence some researchers concluded that two different tests for
diagnosing men and women is the ideal approach. The fluorescent spot test has
the advantage of being less expensive and easy to perform, but is only reliable
for discriminating hemizygous G6PD-deficient men from non-deficient men.
Cytochemical assay is supposed to be the only reliable assay to discriminate
between heterozygous-deficient women and non-deficient women or
homozygous-deficient women. Hence the cytochemical assay is recommended for
women, although it is more expensive and difficult to perform, and a need was
expressed to make it more simplified especially keeping in mind the
affordability issues in the developing countries [32].
Direct testing of the
enzymatic activity of G6PD on a freshly collected blood sample is the most
widely used diagnostic method for diagnosis of deficiency. Methods used include
older tests such as brilliant cresyl blue de-colorization test and
methaemoglobin reduction test [16,17].
The methodology recommended by the International Committee for Standardization
in Hematology is the NADPH fluorescent spot test, which requires a UV
lamp [18,19]. Suboptimal
assay performance due to very wet weather conditions and bloodspot sample
collection on rainy or humid days is known. Drying is an important step,
especially for the storage and consistent elution for the assay [30]. Both of these considerations
may have confounded measurement of G6PD activity, and have led to a greater
proportion of individuals showing lower normal activity or moderate deficiency.
To minimize these issues, it is recommended that filter paper be stored in
zip-lock bags containing silica gel desiccants before being used for blood
collection, and perhaps change of silica gel desiccants frequently after
collection for samples that were not able to be dried sufficiently due to wet
weather conditions [30,31].
These methods all have
shortcomings that limit their use in mass-screening or in field settings [18]. Other methods that do not require UV lamp have been
used for screening studies include the ring method and Sephadex gel MTT-PMS
method [33-36]. These methods are also used
as a diagnostic test prior to primaquine treatment in larger hospitals and
health centers in developing countries, where the necessary facilities and
equipment are available. Other methods that have been described for testing
include cytochemical assays [25], and DNA sequence
analysis of the G6PD gene. The former has the advantage of being a reliable
method for detection of hemizygous deficient males, homozygous deficient
females, or heterozygous deficient females because the G6PD status of
individual erythrocytes is tested [26]. DNA
sequence analysis requires analysis of the whole gene which spans 18kB of
genomic sequence [1,22-25]. However, all of these
tests suffer from limitations that inhibit their utility for in-field
mass-screening purposes, due to factors such as technical expertise required,
expense, duration of test procedure, sensitivity of reagents to light and heat,
low detection threshold, or relatively low throughput capacity [22,24].
Kuwahata, et al.
described a new method modified from the WST8 method optimized to a 96-well
plate format, using dried blood spots with internal standards as controls. This
new method was evaluated to determine the prevalence of G6PD deficiency in
Isabel Province, Solomon Islands [17].
Tests to be Carried Out,
To Confirm the Deficiency of G6PD Enzyme Will Include
There are number of
screening tests to detect G6PD deficiency. Conversion of Nicotinamide Adenine
Dinucleotide Phosphate (NADP) to its reduced form (NADPH) in erythrocytes is
the basis of diagnostic testing for the deficiency. A simple direct test for
G6PD is the fluorescent spot test which has largely replaced the older tests.
This test was developed by Beutler and Mitchell which is based on the fluorescence
of NADPH, generated by an adequate amount of G6PD enzyme [34].
Principle of the Test
The principle of the Ani
Lab Systems Neonatal G6PD assay is based on an enzymatic method intended for
the quantitative determination of glucose 6-phosphate dehydrogenase activity
from dried blood spots. NADP+ is reduced by G6PD (glucose 6-phosphate
dehydrogenase) in the presence of G6-P (Glucose 6-Phosphate), and the rate of
formation of NADPH is proportional to the G6PD activity, and is determined
fluoro metrically (see below). Cold copper reagent is added to stop the
reaction and stabilize the fluorescent complex. Fluorescence is measured (λex
355 nm, λem 460 nm).
· The other tests are direct DNA testing and or
sequencing of the G6PD gene.
· Along with these test other tests to confirm the
deficiency of G6PD include complete blood count and reticulocyte count [27,31]
This test measures the
amount of Glucose-6-Phosphate Dehydrogenase (G6PD) in the Red Blood Cells
(RBCs). G6PD is an enzyme that protects red blood cells from the effects of
oxidation [29,31,33]. If there is insufficient G6PD, the RBCs become more
vulnerable to oxidative damage. If these RBCs are exposed to an oxidative agent
(see a list of drugs and foodstuff to avoid), it changes their cellular
structure, precipitating hemoglobin inside the cells (Heinz Bodies), causing
them to break apart [35,37].
Neonatal Screening
Issues
Neonatal screening, for
this disease, has long been established in many countries and the method most
commonly used is the semi-quantitative method described by Beutler [34] or
modifications to this method. This method was believed to discriminate between
deficient (partial or total deficiency) and normal cases.
Prognosis
Spontaneous recovery
from hemolytic episode is known in the prognosis of this condition. Renal
failure or death following a severe hemolytic event is known as a rare
complication. G6PD deficient individuals do not appear to acquire any illness
more frequently than other people and may have less risk than other people for
acquiring ischemic heart disease and cerebrovascular disease.
Treatment
Prevention is better
than cure
· Avoidance of the drugs and foods that cause
hemolysis
· Vaccination against some common pathogens may
prevent infection induced attacks.
· In the acute phase of hemolysis, patients may
benefit from removal of the spleen as this is an important site of red cell
destruction.
· In case of a severe form, a blood transfusion,
or even an exchange transfusion, may be required.
· Folic acid should be used in any disorder
featuring a high red cell turn over.
Conclusion
Newborns and infants
should be screened for G6PD deficiency when family history, ethnic or
geographic origin, or the timing of appearance of neonatal jaundice suggests
possibility of G6PD deficiency. G6PD deficiency can be diagnosed with a
quantitative spectrophotometric analysis or more commonly by a rapid fluorescent
spot test. The patients with G6PD deficiency should avoid exposure to oxidative
drugs and ingestion of fava beans.
Acknowledgements
We are thankful to our
Managing Director Dr Regupathy Annamalai, M. S, M. Ch for providing us the
internet facility and allowing us to access paid journals contents in the
library, to accomplish this article.
Financial Support: We did not receive any external funding.
Figure 1: The biochemical
reaction catalyzed by the enzyme G6PD.
Class |
Level of deficiency |
Enzyme activity |
Prevalence |
I |
Severe |
Chronic
nonspherocytic hemolytic anemia in presence of normal erythrocyte function |
Uncommon; occurs
across populations |
II |
Severe |
Less than 10% of
normal |
Varies; more common
in Asian and Mediterranean populations |
III |
Moderate |
10 to 60% of normal |
10% of black males
in the United States |
IV |
Mild to none |
60 to 150% of
normal |
Rare |
V |
None |
Greater than 150%
of normal |
Rare |
Table 1: Degrees of G6PD deficiency.
Father | Mother | Inheritance | |
| | Son | Daughter |
Deficient | Unaffected | Unaffected | carriers |
Deficient | Carrier | 50% - G6PD deficient | 50% - G6PD deficient, 50% - carriers |
| | 50% -unaffected | |
Unaffected | Carrier | 50% - G6PD deficient, 50% - unaffected | 50% - carrier |
| | | 50% - unaffected. |
Unaffected | G6PD deficient | G6PD deficient | Carriers |
Unaffected | Unaffected | All children unaffected | |
G6PD deficient | G6PD deficient | All children - G6PD deficient |
Table 2: Inheritance pattern.
Father | |||
Gametes | X1 | Y | |
Mother | X1 | X1 X1 | X1Y |
*X2 | X1 *X2 | *X2Y | |
*Where X2 is diseased allele; X1 is normal X allele. Green color shade represents Female offspring; Red Color shade represents Male offspring. 50% daughters are carriers and 50% daughters are normal. Similarly 50% of the sons are normal and 50% are affected. |
Table 3: Punnet chart showing the different possible offspring if the mother is having diseased X-allele.
| | Father | |
| Gametes | *X2 | Y |
Mother | X1 | X1 X2 | X1Y |
| X1 | X1 X2 | X1Y |
*Where X2 is diseased allele; X1 is normal X allele. Green color shade represents Female offspring; Red Color shade represents Male offspring. Daughters are 100% carriers whereas sons are absolutely normal. |
Table 4: Punnet chart showing the different possible offspring if the father is having diseased X-allele.
| | Father | |
| Gametes | *X2 | Y |
Mother | X1 | X2 X1 | X1Y |
| *X2 | X2 X2 | X2Y |
*Where X2 is diseased allele; X1 is normal X allele. Green color shade represents Female offspring; Red Color shade represents Male offspring. 50% daughters are carriers and 50% daughters are affected. Similarly, 50% of the sons are normal and 50% are affected. |
Table 5: Punnet chart showing the different possible offspring if both the parents are having diseased X-allele.
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