Dominant and Recessive

Autosomal Genetic
Diseases
2322 September
September 2022 2023
Curso Pós-Graduado em Genética e Genómica para Clínicos (GGGC) – 3ª Edição
Genes

• Cell
• Nucleus
• Genetic material
• Chromosomes
• Genes
• DNA
Chromossomes
Gene
 • Genotype - describes the combination of alleles that a
person possesses at a single locus (or at a number of loci)
• Phenotype – observable expression of genotype
• Locus – position of gene in chromosome
• Allele - an individual copy of a gene or other DNA
Background sequence that is carried at a locus on a single
chromosome.
and • Wild-type allele – prevaling version, present in majority
of individuals
terminology • Variant – alteraion of the most prevalente version, rare
or common
• Mutation – rare and patogenic
• Homozygous – having two identicall alleles
• Heterozygous - having two diferent alleles
Genetic desorders
• A genetic disorder or a genetic disease is a
condition which is caused by the error in
DNA.
• Errors in a DNA can be of different type:
• single base
• single gene
• multiple gene
• It can involve the addition or subtraction
of entire chromosome.
The most genetic alterations lead:

A) production of gene product

B) dysfunctional or inactive protein synthesis

Hereditary mutation

• present in egg or sperm

• Present in all body cells

• Since all cells come from that first cell, this type
of mutation is found in all cells (including eggs
or sperm) and therefore can be passed on to
the next generation
Somatic mutation
• An acquired (somatic) mutation does not come
from a parent, but is acquired over time.

• It starts in a cell and, upon cell division, the

mutation is passed on to the new cells.

• This type of mutation is not present in eggs or

sperm, so it is not passed on to the next
generation.

• Acquired mutations are much more frequent

than hereditary mutations.

• Most cancers are caused by acquired mutations.

 Gene disorders

Single gene disorders – monogenic Multiple genetic loci – polygenic

Rare disorders Common

• Chromosomal locus is involved • Multiple genetic loci

(chromosomal loci and loci on
mitochondrial DNA) – Mendelian
Hereditary mutations
 Dominant and recessive phenotypes

• Human monogenic disorder is

determined by a nuclear gene; • it is manifested in the homozygote (who
carries both mutant allele).
• It is manifested in the heterozygote
(who carries a normal allele and a
mutant allele).
Autosomal dominant phenotype
Autosomal recessive phenotype
 Dominant phenotypes

• Disorders are rare

• Individuals are almost always

heterozygotes

• Very rare - affected homozygotes -

parents are both affected
heterozygotes.

• Homozygotes - severe phenotype

than affected heterozygotes.
 Autosomal recessive
inheritance
• Both sex

• Heterozygotes unaffected parents

• The parents - asymptomatic carrier

one mutant allele

• Affects individuals carry two

mutant alleles - one inherited from
each parent.
 Autosomal recessive
inheritance
• The risk one parent transmits the
mutant allele is 1/2, - the risk that
they both transmit the mutant
allele to a child is 1/2 × 1/2 = 1/4)

• When an autosomal recessive

disorder is quite frequent, carriers
is common.
 Autosomal recessive
inheritance
Consanguinity

• A feature of many recessive

disorders

• Especially rare conditions

• Affects individuals often have two

identical mutant alleles because
the parents are close relatives

• Couples are consanguineous.

EXEMPLES
 EXEMPLES

• Li-Fraumeni syndrome;
• Neurofibromatosis;
• Cystic fibrosis
 Li-Fraumeni syndrome

• The Li-Fraumeni Syndrome (LFS) is a hereditary cancer

predisposition syndrome;

• Reported in 1969 by Drs. Frederick Li and Joseph Fraumeni

from the National Cancer Institute.

• The wide range of cancers found in affected families;

• The inherited higher risk of developing cancer across several

generations;

• The relatively early age of the cancer diagnosis with nearly half
of affected individuals having a cancer diagnosis before age 30.
 LFS

Sarcoma family syndrome of Li and

Fraumeni
Other names
Sarcoma, breast, leukemia, and
adrenal gland (SBLA) syndrome

SBLA syndrome
 The TP53 gene at 17p13 has
a central role in cancer
P53
its role as a ‘guardian of the
genome’— DNA damage, cell
cycle arrest or apoptosis.
The TP53 is a transcriptional factor

P53
Transcription factors are proteins involved in the process of
converting, or transcribing, DNA into RNA.
P53 mutations
• Somatic – Mutated in 50% of all tumors

• Hereditary - Li-Fraumeni Syndrome

(LFS)
• Li-Fraumeni syndrome is thought to
occur in 1 in 5,000 to 1 in 20,000
people worldwide.
 P53
• Is a tumour suppressor
protein encoded by the
Tp53 gene.
• When cells are exposed
to damaging conditions –
DNA damage - Tp53 gene
transcription is
upregulated, resulting in
overexpression of p53.
 P53

• A tumor suppressor protein containing

transcriptional activation, DNA binding.

• The encoded protein responds to diverse

cellular stresses to regulate expression of
target genes, thereby inducing cell cycle
arrest, apoptosis, senescence, DNA repair,
or changes in metabolism.
 Alternative splicing of this gene
and the use of alternate
promoters result in multiple
transcript variants and isoforms.
P53
Isoforms have also been shown to
result from the use of alternate
translation initiation codons from
identical transcript variants

p53 mutation within a cell
might have three, not
mutually exclusive, types of
outcome:
1) Mutations abrogate the tumour suppressor function of the
affected TP53 allele, reducing the overall capacity of the cell to
mount a proper p53 response; if both alleles eventually
become mutated, or if the remaining allele is lost - cells will be
totally deprived of anticancer protection by p53.
2) Many common mutp53 isoforms can exert
dominant–negative effects over coexpressed
wtp53, largely by forming mixed tetramers
that are incapable of DNA binding and
transactivation.
3) The emergent mutp53 protein might
possess activities of its own, often not
present in the original wtp53 protein, which
can actively contribute to various aspects of
tumour progression.
P53

Science 2019 vol 365 issue 6453

P53
• p53 protein is expressed at low level in normal cells and at a high level in a variety of transformed cell
lines, which contributes to transformation and malignancy;

• p53 is a DNA-binding protein containing transcription activation;

• Mutations in tumour suppressor genes result in LOF that are typically associated with deletions and
mutations that create premature stop codons and thus truncation or loss of the encoded protein;

• Mutations are typically missense mutations that affect amino acids throughout the central DNA-
binding domain;

• 10 hotspot mutations account for ~50% of the mutations found in p53.

 TP53

Multiple p53 variants due to

alternative promoters and
multiple alternative splicing have
been found.
These variants encode distinct
isoforms, which can regulate p53
transcriptional activity.

https://p53.iarc.fr/p53isoforms.aspx
Neurofibromatosis
 • Neurofibromatosis (NF), a type of syndrome with
neurological and cutaneous manifestations;
• It is a rare genetic disorder that typically causes
benign tumors of the nerves and growths in
other parts of the body, including the skin.
Neurofibromatosis
• Associated with neurological problems;
• There are two major types: neurofibromatosis
type I (NF1) and neurofibromatosis type II (NF2).
Neurofibromatosis

• NF1 manifests itself at birth or during early childhood.

• NF1 is characterized by multiple light brown (café-au-lait) spots concentrated in the groin and
underarms and benign tumors under the skin.
• People with NF1 may develop tumors in the brain, on the cranial nerves or involving the spinal
cord.
• NF2 may appear during childhood, adolescence or early adulthood.
• NF2 is primarily characterized by benign tumors of the nerves that transmit sound impulses
and balance signals from the inner ears to the brain. Tumors commonly affect both the left and
right (bilateral) hearing and balance (vestibulocochlear) nerves.
• The most common form is neurofibromatosis 1 (96%), followed by neurofibromatosis 2 (3%)
 NF1

• An autosomal dominant tumour predisposition syndrome most readily characterized by the

development of multiple neurofibromas of the peripheral nerves

• Malignancies associated with NF1 include malignant peripheral nerve sheath tumours, gliomas,
leukaemia, pheochromocytomas, gastrointestinal, etc
Clinical
manifestations

Fan Yang et al 2018 OncoTargets and Therapy Volume 11:919-932

NF1

The NF1 gene is located on chromosome 17q11.2, which encodes for a protein
known as neurofibromin
 NF1

• Neurofibromin belongs to the GTPase-activating

family of tumor suppressor proteins that regulate
the function of the RAS/MAPK signaling and
mechanistic target of rapamycin (mTOR)
pathways.
NF1
 NF1

• Tipe of NF1 mutations:

• deletion of the entire gene

• 1,500 different mutations of the NF1

• Nonsense, frameshift, and point mutations have all been identified with the majority of the mutations
leading to a truncated form of the protein.
Cystic Fibrosis
• caused by mutations in a single gene
• in the cystic fibrosis transmembrane
conductance regulator (CFTR) gene
• Its function is to create channels on the cell
surface to allow the movement of chloride in
and out of the cell.
• When the CFTR protein functions properly,
the balance of chloride and fluid at the cell
surface remains normal.
• More than 1,700 different mutations in the
CFTR gene that can cause CF
Cystic Fibrosis
 70-80% of CFTR patientes have a
phenylalanine deletion at the
position 508 (ΔF508)

Cystic 50% homozygous conditions

Fibrosis
25-30% in conbination with other
mutations
 • 90% - respitarory problems, manifested in
frist mounths: bronchiolitis or obstrutive
bronchitis, bronchopneumonia, etc
Clinical
features • 85% exocrine pancreatic insuficiency –
pancreatic tubes obstruction
• Malabsorption of nutrientes - lack of pancreatic
enzymes
Questions?