Genetic Disorders Flashcards
The lifetime frequency of genetic diseases is
670 per 1000
It is estimated
that 50% of spontaneous abortuses during the early months of
gestation have a
a demonstrable chromosomal abnormality; there
are, in addition, numerous smaller detectable errors and many
other genetic lesions that are only now coming into view thanks
to advances in DNA sequencing
About ________of all newborn infants
possess a gross chromosomal abnormality and serious disease
with a significant genetic component develops in approximately
__________of individuals younger than age 25 years.
1%; 5%
Disorders related to mutations in single genes with large
effects.
These mutations cause the disease or predispose to the
disease and with some exceptions, like hemoglobinopathies, are
typically not present in the normal population. Such mutations and
their associated disorders are highly penetrant, meaning that
the presence of the mutation is associated with the disease in a large proportion of individuals.
these diseases are
caused by single-gene mutations, they usually follow the
The mendelian pattern of inheritance and are also referred to as Mendelian disorders
Chromosomal disorders
These arise from structural or
numerical alteration in the autosomes and sex chromosomes.
Like monogenic disease they are uncommon but associated
with high penetrance.
Complex multigenic disorders
hey are caused
by interactions between multiple variant forms of genes and
environmental factors. Such variations in genes are common
within the population and are also called polymorphisms
no single susceptibility gene is necessary or sufficient to
produce the disease. It is only when several such
polymorphisms are present in an individual that disease occurs,
hence the term
Multigenic or polygenic
Thus, unlike mutant
genes with large effects that are highly penetrant and give rise
to Mendelian disorders
each polymorphism has a small effect
and is of low penetrance
multifactorial disorders
In this category are some of the
most common diseases that afflict humans, including atherosclerosis, diabetes mellitus, hypertension, and
autoimmune diseases. Even normal traits such as height and weight are governed by polymorphisms in several genes
Mutations
A mutation is defined as a permanent change in the DNA. Mutations that affect germ cells are transmitted to the
progeny and can give rise to inherited diseases.
Point mutations within coding sequences
A point mutation
is a change in which a single base is substituted with a different
base. It may alter the code in a triplet of bases and lead to the
replacement of one amino acid by another in the gene product.
missense mutations
these mutations alter the meaning of the sequence of
the encoded protein
If the substituted amino acid is biochemically similar to the
original, typically it causes little change in the function of the
protein and the mutation is called a
conservative
nonconservative
mutation replaces the normal amino acid with a biochemically
different one
An excellent example of this type is the sickle
mutation affecting the β-globin chain of hemoglobin (Chapter
14). Here the nucleotide triplet CTC (or GAG in mRNA), which
encodes glutamic acid, is changed to CAC (or GUG in mRNA),
which encodes valine. This single amino acid substitution alters
the physicochemical properties of hemoglobin, giving rise to
sickle cell anemia
point mutation
change an amino acid codon
to a chain terminator, or stop codon (nonsense mutation).
Taking again the example of β-globin, a point mutation affecting
the codon for glutamine (CAG) creates a stop codon (UAG) if U
is substituted for C (Fig. 5-1). This change leads to premature
termination of β-globin gene translation, and the short peptide
that is produced is rapidly degraded. The resulting deficiency of
β-globin chains can give rise to a severe form of anemia called
β -thalassemia
mutations within noncoding sequences.
Deleterious effects
may also result from mutations that do not involve the exons.
Recall that transcription of DNA is initiated and regulated by
promoter and enhancer sequences
Point mutations
or deletions involving these regulatory sequences may interfere
with binding
of transcription factors and thus lead to a marked reduction in or total lack of transcription.]
Such is the case in
certain forms of hereditary anemias called thalassemias
point mutations within introns may
lead to
defective splicing of intervening sequences. This, in
turn, interferes with normal processing of the initial mRNA
transcripts and results in a failure to form mature mRNA.
Therefore, translation cannot take place, and the gene product
is not synthesized.
Deletions and insertion
Small deletions or insertions
involving the coding sequence can have two possible effects on
the encoded protein.
If the number of base pairs involved is
three or a multiple of three,
the reading frame will remain
intact, and an abnormal protein lacking or gaining one or more
amino acids will be synthesized (Fig. 5-2). If the number of
affected coding bases is not a multiple of three, this will result
in an alteration of the reading frame of the DNA strand,
producing what is referred to as a frameshift mutation
Single-base deletion at the ABO (glycosyltransferase)
locus, leading to a frameshift mutation responsible for the O allele
Cystic Fibrosis is not frame shift, why?
: 3 base deletion causes formation of a protein that lacks 508 aa (phenylalanine) this is not a Frameshift mutation
Four-base insertion
in the hexosaminidase A gene,
leading to a frameshift mutation. This mutation is the major cause
of Tay-Sachs disease in Ashkenazi Jews
Trinucleotide-repeat mutations
Trinucleotide-repeat
mutations belong to a special category of genetic anomaly.
These mutations are characterized by the amplification of a
sequence of three nucleotides.
fragile X
syndrome
prototypical of this category of disorders, there are
250 to 4000 tandem repeats of the sequence CGG within a gene
called familial mental retardation 1 (FMR1). In normal
populations the number of repeats is small, averaging 29. Such
expansions of the trinucleotide sequences prevent normal
expression of the FMR1 gene, thus giving rise to mental
retardation
the distinguishing feature of trinucleotide-repeat mutations
is that they are dynamic (i.e., the degree of amplification increases during gametogenesis). These features,
discussed in greater detail later, influence the pattern of
inheritance and the phenotypic manifestations of the diseases
caused by this class of mutation.
three major categories of genetic disorders
(1) disorders related to mutant genes of large effect, (2) diseases with multifactorial inheritance (3) chromosomal disorders
To these three well-known categories must be added a heterogeneous group of
Single-gene disorders with nonclassic patterns of inheritance.
This group includes disorders resulting from triplet-repeat
mutations, those arising from mutations in mitochondrial DNA
(mtDNA), and those in which the transmission is influenced by
genomic imprinting or gonadal mosaicism.
They don’t follow Mendelian inheritance
Hereditary disorders
by definition, are
derived from one’s parents and are transmitted in the germ line
through the generations and therefore are familial
congenital
simply implies “born with.”
Some congenital diseases
are not genetic;
for example, congenital syphilis. Not all genetic diseases are congenital; individuals with Huntington disease, for
example, begin to manifest their condition only after their 20s or 30s.
Mendelian Disorders
Virtually all Mendelian disorders are the result of mutations in
single genes that have large effects
it is estimated that every individual is a carrier of ________
deleterious genes
five to eight a number originally estimated from studies of
populations that appear to be borne out by genomic sequencing
of normal individuals.
Most of these are recessive and therefore
do not have serious phenotypic effects.
About 80% to 85% of
these mutations are familial. The remainder represents new
mutations acquired de novo by an affected individual.
Some autosomal mutations produce partial expression in the
heterozygote and full expression in the homozygotes
This is referred to as the
sickle cell trait to differentiate it from full-blown sickle cell
anemia
Sickle cell anemia is caused by the substitution of normal hemoglobin (HbA) by hemoglobin S (HbS). When an individual is homozygous for the
mutant gene, all the hemoglobin is of the abnormal, HbS, type, and even with normal saturation of oxygen the disorder is fully expressed (i.e., sickling deformity of all red cells and hemolytic
anemia). In the heterozygote, only a proportion of the
hemoglobin is HbS (the remainder being HbA), and therefore
red cell sickling occurs only under unusual circumstances, such
as exposure to lowered oxygen tension
in some cases both of the alleles of a gene pair
contribute to the phenotype
codominance.
Histocompatibility and blood group antigens are good examples
of codominant inheritance.
A single mutant gene may lead to many end effects, termed
pleiotropism; conversely, mutations at several genetic loci may produce the same trait (genetic heterogeneity)
Sickle cell
anemia is an example of pleiotropism.
mom, blood type OO, father also O can A be produced?
yES
In this hereditary disorder
not only does the point mutation in the gene give rise to HbS,
which predisposes the red cells to hemolysis, but also the
abnormal red cells tend to cause a logjam in small vessels,
inducing
splenic fibrosis, organ infarcts, and bone
changes. The numerous differing end-organ derangements are
all related to the primary defect in hemoglobin synthesis.
profound childhood deafness
an apparently
the homogeneous clinical entity results from many different types of
autosomal recessive mutations
