KAPLAN_USMLE_STEP_1_LECTURE_NOTES_2018_BIOCHEMISTRY_and_GENETICS

Part II ● Medical Genetics

Note

Major types of single-gene mutations are:

•Missense

•Nonsense

•Deletion

•Insertion

•Frameshift

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For example, the β-globin gene encodes a protein (β-globin). It has been mapped to chromosome 11p15.5 indicating its locus, a specific location on chromosome 11. Throughout human history there have been many mutations in the β-globin gene, and each mutation has created a new allele in the population. The β-globin locus is therefore polymorphic. Some alleles cause no clinical disease, but others, like the sickle cell allele, are associated with significant disease. Included among the disease-causing alleles are those associated with sickle cell anemia and several associated with β-thalassemia.

Genotype

The specific DNA sequence at a locus is termed a genotype. In diploid somatic cells a genotype may be:

•Homozygous if the individual has the same allele on both homologs (homologous chromosomes) at that locus.

•Heterozygous if the individual has different alleles on the two homologs (homologous chromosomes) at that locus.

Phenotype

The phenotype is generally understood as the expression of the genotype in terms of observable characteristics.

Mutations

A mutation is an alteration in DNA sequence (thus, mutations produce new alleles). When mutations occur in cells giving rise to gametes, the mutations can be transmitted to future generations. Missense mutations result in the substitution of a single amino acid in the polypeptide chain (e.g., sickle cell disease is caused by a missense mutation that produces a substitution of valine for glutamic acid in the β-globin polypeptide). Nonsense mutations produce a stop codon, resulting in premature termination of translation and a truncated protein. Nucleotide bases may be inserted or deleted. When the number of inserted or deleted bases is a multiple of 3, the mutation is said to be in-frame. If not a multiple of 3, the mutation is a frameshift, which alters all codons downstream of the mutation, typically producing a truncated or severely altered protein product. Mutations can occur in promoter and other regulatory regions or in genes for transcription factors that bind to these regions. This can decrease or increase the amount of gene product produced in the cell. (For a complete description of these and other mutations, see Section I, Chapter 4: Translation; Mutations.)

Mutations can also be classified according to their phenotypic effects. Mutations that cause a missing protein product or cause decreased activity of the protein are termed loss-of-function. Those that produce a protein product with a new function or increased activity are termed gain-of-function.

Recurrence risk

The recurrence risk is the probability that the offspring of a couple will express a genetic disease. For example, in the mating of a normal homozygote with a heterozygote who has a dominant disease-causing allele, the recurrence risk for each offspring is 1/2, or 50%. It is important to remember that each reproductive event is statistically independent of all previous events. Therefore, the recurrence risk remains the same regardless of the number of previously affected or unaffected offspring. Determining the mode of inheritance of a disease

MAJOR MODES OF INHERITANCE

Autosomal Dominant Inheritance

High-Yield

Note

Autosomal Dominant Diseases

•Familial hypercholesterolemia (LDL receptor deficiency)

•Huntington disease

•Neurofibromatosis type 1

•Marfan syndrome

•Acute intermittent porphyria

Figure II-1-2. Autosomal Dominant Inheritance

A Punnett square: Affected offspring (Aa) are shaded.

Figure II-1-3. Recurrence Risk for the Mating of Affected Individual (Aa) with a Homozygous Unaffected Individual (aa) using a Punnett Square

Important features that distinguish autosomal recessive inheritance:

•Because autosomal recessive alleles are clinically expressed only in the homozygous state, the offspring must inherit one copy of the diseasecausing allele from each parent.

•In contrast to autosomal dominant diseases, autosomal recessive diseases are typically seen in only one generation of a pedigree.

•Because these genes are located on autosomes, males and females are affected in roughly equal frequencies.

Most commonly, a homozygote is produced by the union of two heterozygous (carrier) parents. The recurrence risk for offspring of such matings is 25%.

A consanguineous mating has produced two affected offspring.

Figure II-1-4. Pedigree for an Autosomal Recessive Disease

Determining the Recurrence Risk for an Individual Whose Phenotype Is Known. In Figure II-1-4, individual IV-1 may wish to know his risk of being a carrier. Because his phenotype is known, there are only 3 possible genotypes he can have, assuming complete penetrance of the disease-producing allele. He cannot be homozygous for the recessive allele (aa). Two of the remaining 3 possibilities are carriers (Aa and aA), and one is homozygous normal (AA). Thus, his risk of being a carrier is 2/3, or 0.67 (67%).

The affected genotype (aa) is shaded.

Figure II-1-5. Recurrence Risk for the Mating of

Two Heterozygous Carriers (Aa) of a Recessive Mutation

Properties of X-linked recessive inheritance

Because males have only one copy of the X chromosome, they are said to be hemizygous (hemi = “half”) for the X chromosome. If a recessive diseasecausing mutation occurs on the X chromosome, a male will be affected with the disease.

•Because males require only one copy of the mutation to express the disease and females require 2 copies, X-linked recessive diseases are seen much more commonly in males than in females.

Note

Autosomal Recessive Diseases

•Sickle cell anemia

•Cystic fibrosis

•Phenylketonuria (PKU)

•Tay-Sachs disease (hexosaminidase A deficiency)

Note

Cystic fibrosis is an important topic on the exam.

Part II ● Medical Genetics

Note

X-Linked Recessive Diseases

•Duchenne muscular dystrophy

•Lesch-Nyhan syndrome (hypoxanthine-guanine phosphoribosyltransferase [HGPRT] deficiency)

•Glucose-6-phosphate dehydrogenase deficiency

•Hemophilia A and B

•Red-green color blindness

•Menke’s disease

•Ornithine transcarbamoylase (OTC) deficiency

•SCID (IL-receptor γ-chain deficiency)

•Skipped generations are commonly seen because an affected male can transmit the disease-causing mutation to a heterozygous daughter, who is unaffected but who can transmit the disease-causing allele to her sons.

•Male-to-male transmission is not seen in X-linked inheritance; this helps distinguish it from autosomal inheritance.

Figure II-1-6. X-Linked Recessive Inheritance

Recurrence risks

Figure II-1-7 shows the recurrence risks for X-linked recessive diseases.

•Affected male–homozygous normal female: All of the daughters will be heterozygous carriers; all of the sons will be homozygous normal.

•Normal male–carrier female: On average, half of the sons will be affected and half of the daughters will be carriers. Note that in this case, the recurrence rate is different depending on the sex of the child. If the fetal sex is known, the recurrence rate for a daughter is 0, and that for a son is 50%. If the sex of the fetus is not known, then the recurrence rate is multiplied by 1/2, the probability that the fetus is a male versus a female. Therefore if the sex is unknown, the recurrence risk is 25%.

A.Affected male–homozygous normal female

(X chromosome with mutation is in lower case)

B.Normal male–carrier female

Figure II-1-7. Recurrence Risks for X-Linked Recessive Diseases

X inactivation

Normal males inherit an X chromosome from their mother and a Y chromosome from their father, whereas normal females inherit an X chromosome from each parent. Because the Y chromosome carries only about 50 protein-coding genes and the X chromosome carries hundreds of protein-coding genes, a mechanism must exist to equalize the amount of protein encoded by X chromosomes in males and females. This mechanism, termed X inactivation, occurs in the blastocyst (~100 cells) during the development of female embryos. When an X chromosome is inactivated, its DNA is not transcribed into mRNA, and the chromosome is visualized under the microscope as a highly condensed Barr body in the nuclei of interphase cells. X inactivation has several important characteristics:

•It is random—in some cells of the female embryo, the X chromosome inherited from the father is inactivated, and in others the X chromosome inherited from the mother is inactivated. Like coin tossing, this is a random process. As shown in Figure II-1-6, most women have their paternal X chromosome active in approximately 50% of their cells and the maternal X chromosome active in approximately 50% of their cells. Thus, females are said to be mosaics with respect to the active X chromosome.

•It is fixed—once inactivation of an X chromosome occurs in a cell, the same X chromosome is inactivated in all descendants of the cell.

•It is incomplete—there are regions throughout the X chromosome, including the tips of both the long and short arms, that are not inactivated.

•X-chromosome inactivation is permanent in somatic cells and reversible in developing germ line cells. Both X chromosomes are active during oogenesis.

•All X chromosomes in a cell are inactivated except one. For example, females with 3 X chromosomes in each cell (see Chapter 3) have two X chromosomes inactivated in each cell (thus, two Barr bodies can be visualized in an interphase cell). X-chromosome inactivation is thought to be mediated by >1 mechanism.

•A gene called XIST has been identified as the primary gene that causes X inactivation. XIST produces an RNA product that coats the chromosome, helping produce its inactivation.

•Condensation into heterochromatin

•Methylation of gene regions on the X chromosome

Chapter 1 ● Single-Gene Disorders

Note

X inactivation occurs early in the female embryo and is random, fixed, and incomplete. In a cell, all X chromosomes but one are inactivated.

Note

Genetic mosaicism is the presence of 2 or more cell lines with different karyotypes in an individual. It arises from mitotic nondisjunction. The number of cell lines that develop and their relative proportions are influenced by the timing of nondisjunction during embryogenesis and the viability of the aneuploid cells produced.

Part II ● Medical Genetics

Blastocyst ~100 cells

Females

Number of

5/95 50/50 95/5

Percentage of cells with paternal/maternal X active

There are relatively few diseases whose inheritance is classified as X-linked dominant. Fragile X syndrome is an important example. In this condition, females are differently affected than males, and whereas penetrance in males is 100%, that in females is approximately 60%. The typical fragile X patient described is male.

As in X-linked recessive inheritance, male–male transmission of the diseasecausing mutation is not seen.

•Heterozygous females are affected. Because females have 2 X chromosomes (and thus 2 chances to inherit an X-linked diseasecausing mutation) and males have only one, X-linked dominant diseases are seen about twice as often in females as in males.

•As in autosomal dominant inheritance, the disease phenotype is seen in multiple generations of a pedigree; skipped generations are relatively unusual.

•Examine the children of an affected male (II-1 in the figure below). None of his sons will be affected, but all of his daughters have the disease (assuming complete penetrance).

Figure II-1-9. X-Linked Dominant Inheritance

Clinical Correlate

Fragile X Syndrome

Males: 100% penetrance

•Mental retardation

•Large ears

•Prominent jaw

•Macro-orchidism (usually postpubertal)

Females: 60% penetrance

• Mental retardation

Note

The penetrance of a disease-causing mutation is the percentage of individuals who are known to have the disease-causing genotype who display the disease phenotype (develop symptoms).

Part II ● Medical Genetics

Note

X-Linked Dominant Diseases

•Hypophosphatemic rickets

•Fragile X syndrome

Mitochondrial Inheritance

High-Yield