This document discusses the molecular, biochemical, and cellular basis of genetic diseases. It covers the central dogma of DNA to protein, classes of proteins, and examples of diseases involving enzymes, receptors, transport proteins, and structural proteins. Specific diseases discussed include phenylketonuria, retinitis pigmentosa, thalassemia, Ehlers-Danlos syndrome, Alzheimer's disease, Huntington's disease, and Parkinson's disease. The document also provides molecular pathways and assigns students to write essays on different genetic diseases.

1. z
The molecular,
biochemical, and
cellular basis of
genetic disease
Dr. dr. Mitayani, M.Si. Med.

2. z CENTRAL DOGMA
 DNA (gene) 
mRNA  amino
acid protein

3. z
 https://www.youtube.com/watch?v=xHxsVRM-pS8

4. z
classes of proteins
 Hormonal protein
 Enzymatic protein
 Structural protein
 Defensive protein
 Storage protein
 Transport protein
 Receptor protein
 Contractile protein

5. z
Disease involving enzymes
 Inborn error of metabolisms are a heterogeneous group of
disorders which involve failure of the metabolic pathways
involved in either the break-down or storage of carbohydrates,
fatty acids, and proteins.
 Very rare, 1:2500 births
 Caused by mutations in genes coding for proteins that function
in metabolism.
 Majority of the IEMs are inherited in an autosomal recessive
manner.

6. z
Disease involving enzymes
Amno acid disorder Urea cycle disorders
Organic acid metabolism disorder Carbohydrate disorders
Fatty acid oxidation disorder Peroxisomal disorders
Lysosomal storage diseases Mitochondrial disorders
Example: Phenylketonuria
Mutations in the PAH gene causes the reduction or loss of phenylalanine hydroxylase
enzyme.
Result: phenylalanine from the diet is not processed effectively. As a result, this
amino acid can build up to toxic levels in the blood and other tissues. Because nerve
cells in the brain are particularly sensitive to phenylalanine levels, excessive amounts
of this substance can cause brain damage.

7. z
Molecular pathway of Phenylketonuria
a b
a: phenylalanine hydroxylase
b: DOPA carboxylase
c: homogentisic acid oxidase
d: thyroid peroxidase
d
c

8. z
Defect in receptor protein
 Receptors is proteins either inside a cell or on its surface which
receive a signal.
 Retinitis pigmentosa (RP): degeneration of photoreceptors
caused by mutations in Rhodopsin. Presently, about 70 genes
have been identified to be associated with RP.

9. z
Molecular pathway of Retinitis
pigmentosa

10. z
Transport defects
 Example: protein globin for the O2 transport
 Mutation in beta globin gene  Thalassemia beta

11. z
Molecular pathway of Thalassemia

12. z
Disorder of structural proteins
 Structural proteins are proteins that living organisms use to
maintain their shape or structural integrity. Some common
structural proteins are keratin, collagen, actin, and myosin.
 Ehlers-Danlos syndrome: genetic disease due to defect in
collagen.
https://ejournal2.undip.ac.id/index.php/jbtr/article/view/4531/360
5

13. z

14. z
 (I) haploinsufficiency for COL5A1 is uncompensated and leads to a reduction in COL5A1
mRNA and α1(V) procollagen chains. This accounts for 30–50% of classical EDS cases.
 (II) Many proline and lysine residues in the translated procollagen chains are hydroxylated
by lysyl- and proline hydroxylases. Hydroxylation is essential for subsequent crosslinking
and lysyl-hydroxylase deficiency causes the kyphoscoliosis form of EDS.
 (III) Procollagen α-chains are assembled into trimers within the rough endoplasmic
reticulum (RER). Mutations in COL3A1 that interrupt the triple helical structure prevent
normal processing and secretion of collagen III, causing the vascular form of EDS.
 (IV) In the ECM, the NH2- and COOH-terminal propeptides are cleaved by specific
peptidases. Dominant mutations in COL1A1 and COL1A2 can prevent cleavage and cause
arthrochalasia, while recessive loss of the N-procollagen peptidase cause dermatosparaxis.
 (V) Collagen molecules self-assemble into heterotypic fibrils. Dominant-negative mutations
in COL5A1 and COL5A2 alter fibril assembly and cause some cases of classical EDS.

15. z
Ehlers-Danlos Syndrome

16. z
Neurodegenerative disorder
 Neurodegenerative diseases cause progressive loss of brain
functions.
 Aging is a common risk factor.
 Many neurodegenerative disorders are characterized by the
accumulation of misfolded proteins or peptide fragments in the
brain and spinal cord.
 Neuronal pathways altered in various neurodegenerative diseases:
protein folding and quality control, autophagy and lysosomal
dysfunction, mitochondrial damage and homeostasis, protein
seeding and propagation, stress granules, and synaptic toxicity

17. z
Neurodegenerative disorder
 Alzheimer’s disease (AD), vascular dementia, Huntington’s
disease (HD), Parkinson’s disease (PD), spinocerebellar ataxias
(SCA).
 HD and SCA: single-gene disorder, triple repeat expansions.
 AD: dominant mutations in amyloid precursor protein (APP),
presenilin 1 (PS1), and PS2.

18. z
Neurodegenerative disorder

19. z
TUGAS INDIVIDU
 Mahasiswa diminta membuat essay mengenai satu penyakit
genetik (selain contoh yang telah diberikan di kuliah ini).
 Maksimal 3 halaman A4, diketik.
 Isi essay:
 1. Definisi,
 2. letak gangguan genetik (lokasi gen, kromosom, jenis mutasi)
 3. Mekanisme molekuler dari gangguan di gen hingga timbul
penyakit

20. z
TUGAS INDIVIDU
 Absen 1: Disease involving enzyme
 Absen 2: disease involving receptor
 Absen 3: disease involving transport protein
 Absen 4: disease involving structural protein
 Absen 5: Disease involving enzyme
 Absen 6: disease involving receptor
 Absen 7: disease involving transport protein
 Absen 8: disease involving structural protein


21. z
Thank you