-1JustinaColeman

Biology 121 section jm

November 16, 2009

Human Disorders Due to Chromosomal Alterations

Alterations of chromosome number and structure are associated with a number of serious

human disorders. Nondisjunction of sex chromosomes produces a variety of aneuploid

conditions (chromosomal aberrations in which one or more chromosomes are present in extra

copies or are deficient in number). Most of these conditions appear to upset genetic balance less

than aneuploid conditions involving autosomes. The nondisjunction in meiosis results in

aneuploidy in gametes and any resulting zygotes.

Down syndrome, affects one out of every 700 children and seems to increase with the

age of the mother. While the disorder occurs in just 0.04% of children born to women under the

age of 30, the risk climbs to 0.92% for mothers of the age of 40 and older. Most cases result

from nondisjunction during meiosis I, and some research points to an age-dependent abnormality

in a meiosis checkpoint that normally delays anaphase until all the kinetochores are attached to

the spindle for (e.g. the M phase checkpoint of the mitotic cell cycle). Down syndrome is

usually the result of an extra chromosome 21, so that each body cell has a total 47 chromosomes.

Because the cells are trisomic for chromosome 21, Down syndrome is often called trisomy 21.

The characteristics are flat facial features, short stature, heart defects, eyelid fold, stubby fingers,

and large fissured tongue, round head, distinctive palm crease, leukemia, Alzheimer’s disease

and mental retardation. On average people with Down syndrome live shorter life spans than

normal, but some do live to middle age or beyond. Most are sexually underdeveloped and

sterile.
 Males born with an extra X sex chromosome, producing XXY, occurs in one out of every

1,000 males. This condition is known as Klinefelter syndrome 47 or XXY syndrome. One in

every 500 males has an extra X chromosome but do not have the syndrome. The cause is an

extra X chromosome that is retained due to a nondisjunction event during meiosis. The principal

effects are development of small testicles and reduced fertility. The term hypogonadism in XXY

symptoms is often misinterpreted to mean small testicles or small penis; in fact, it means

decreased testicular hormone/endocrine function. Because of this hypogonadism, patients will

often have a low serum testosterone level but high serum follicle stimulating hormone and

luteinizing hormone levels. Despite this misunderstanding of the term, however, it is true that

XXY men often have microorchidism (small testicles). Some degree of language learning

impairment may be present and neuropsychological testing often reveals deficits in executive

functions. In adults there is a lanky, youthful build and facial appearance, and some degree of

increased breast tissue. It is currently thought that rare X-linked recessive conditions occur

less frequently in XXY males than in normal XY males, since these conditions are transmitted by

genes on the X chromosome, and people with two X chromosomes are typically only carriers

rather than affected by these X-linked recessive conditions

Turner syndrome is a chromosomal disorder of females in which all or part of one of the

sex chromosomes is absent. Typical females are born with 2 X chromosomes, but in Turner

syndrome one of those sex chromosomes is missing (XO) or has other abnormalities. In some

cases the missing chromosome is present in some cells but not in others, a condition referred to

as mosaicism or Turner mosaicism. Turner syndrome occurs in one out of 2500 girls. The

characteristic physical abnormalities are short stature, broad chest, and low hairline, low set ears
and webbed necks. Females born with Turner syndrome have gonadal dysfunction (non working

ovaries), which results in amenorrhea (absence of menstrual cycle) and sterility. Other

symptoms may include a small lower jaw, cubitus valgus (turned out elbows), soft upturned

nails, and drooping eyelids. It is unknown if there is a genetic predisposition present that causes

the abnormality, though most researchers and doctors treating Turners syndrome agree that this is

highly unlikely. There is currently no known cause for Turner’s syndrome, though there are

several theories surrounding the subject.

Justina Coleman

Biology 121 section jm

November 16, 2009

Sickle Cell disease

Sickle-cell anemia is the name of a specific form of sickle cell disease in which there is a

homozygosis for the mutation that causes HbS. Sickle cell anemia is also referred to as HbSS,

SS disease, hemoglobin S or permutations. In heterozygous people who have only one sickle

gene and one normal adult hemoglobin gene, is referred to as HbAS or sickle cell trait. The

term “disease” is applied, because the inherited abnormality causes a pathological condition that

can lead to death and severe complications. In people heterozygous for HgbS (carriers of

sickling hemoglobin) the polymerization problems are minor, because the normal allele is able to

produce 50% of the hemoglobin. In people homozygous for HgbS, the presence of long chain

polymers of HbS distort the shape of the red blood cell from a smooth donut like shape to ragged

and full of spikes, making it fragile and susceptible to breaking within capillaries. Carriers have

symptoms only if they are deprived of oxygen or while severely dehydrated. Under normal

circumstances, these painful crises occur 0.8 times per year per patient. The sickle cell disease

occurs when the seventh amino acid, glutamic acid, is replaced by valine to change its structure

and function.

The gene defect is a known mutation of a single nucleotide of the B-globin gene, which

results in glutamate being substituted by valine at position 6. Hemoglobin S with this mutation

is referred to as HbS, as opposed to the normal adult HbA. The genetic disorder is due to the
mutation of a single nucleotide, from GAG to GTG condon mutation. This is normally a benign

mutation, causing no apparent effects on the secondary, tertiary, or quaternary structure of

hemoglobin in conditions of normal oxygen concentration. What it does allow for, under

conditions of low oxygen concentration, is the polymerization of the Hbs itself. The deoxyribose

form of hemoglobin exposes a hydrophobic patch to the protein between the E and F helices.

The hydrophobic residues of the valine at position 6 of the beta chain in hemoglobin are able to

associate with the hydrophobic patch, causing hemoglobin S molecules to aggregate and form

fibrous precipitates.

The loss of red blood cell elasticity is central to the pathophysiology of sickle cell

disease. Normal red blood cells are quite elastic, which allows the cells to deform to pass

through capillaries. In sickle cell disease, low oxygen tension promotes red blood cell sickling

and repeated episodes of sickling damage the cell membrane and decrease the cells elasticity.

These cells fail to return to normal shape when normal oxygen tension is restored. As a

consequence, these rigid blood cells are unable to deform as they pass through narrow

capillaries, leading to vessel occlusion and ischemia.

The actual anemia of the disease is caused by hemolysis, the destruction of the red cells

inside the spleen, because of their misshape. Although the bone marrow attempts to compensate

by creating new red cells, it does not match the rate of destruction. Healthy red blood cells

typically live 90-120 days, but sickle cells only survive 10-20 days.

The allele responsible for sickle cell anemia is autosomal incomplete dominant and can

be found on the short arm of chromosome 11. A person receives the defective gene from both

the father and mother develops the disease; a person that receives one defective and one healthy
allele remains healthy, but can pass on the disease and is known as a carrier. If two parents who

are carriers have a child there is a one-in-four chance of their child developing the disease and a

one-in-two chance of their child being just a carrier.

Sickle cell conditions are inherited from parents in much the same way as blood type,

hair color, eye color and other physical traits. The types of hemoglobin genes are inherited from

their parents. If a parent has sickle cell anemia (SS) and the other has sickle cell trait (AS), there

is a 50% chance of a child having sickle cell disease (SS) and a 50% chance of a child having

sickle cell trait (AS). When both parents have sickle cell trait (AS) a child has a 25% chance

(1of 4) of sickle cell disease (SS).