Molecular biology of inherited diseases
Some common inherited disorders by pattern of inheritance
Pattern | Disorder | Genes |
Autosomal recessive | α thalassemia β thalassemia Cystic fibrosis Gaucher disease Hereditary hemochromatosis Spinal muscular atrophy Tay-Sachs disease | α-globin β-globin CFTR Glucocerebrosidase HFE SMN-telomeric Hexosaminidase A |
Autosomal dominant | Charcot-Marie Tooth disease, type1A HNPCC Hereditary pancreatitis Hereditary breast cancer Huntington disease Marfan syndrome Myotonic dystrophy Neurofibromatosis, type 1 Neurofibromatosis, type 2 Osteogenesis imperfecta | Peripheral myelin protein 22 MSH-2, MLH-1, PMS-1, PMS-2 Cationic trypsinogen BRCA1/BRCA2 Huntingtin Fibrillin Myotonin kinase Neurofibromin MERLIN Type 1 collagen, α1 or α2 |
X-linked recessive | Duchenne/Becker muscular dystrophy Fragile X syndrome Glucose 6-phosphate dehydrogenase deficiency Hemophilia A Hemophilia B | Dystrophin FMR-1 G6PD Factor VIII Factor IX |
X-linked dominant | Hypophosphatemic rickets | PHEX |
Mitochondrial | Leber’s hereditary optic neuropathy (LHON) MERFF, MELAS, NARP, KSS |
CFTR : cystic fibrosis transmembrane conductance regulator
MERFF : mitochondrial encephalopathy with ragged red muscle fibers
MELAS : mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes
NARP : neurogenic muscle weakness, ataxia, and retinitis pigmentosa
KSS : Kearn’s-Sayre syndrome
Common disorders associated with different types of genetic mutations
Type | Disease | Genes |
Point mutations | α thalassemia β thalassemia Cystic fibrosis Gaucher disease Hereditary hemochromatosis Duchenne/Becker muscular dystrophy Hemophilia A Neurofibromatosis, type 1 Sickle cell anemia Hypercoagulability – factor V Leiden Hypercoagulability – factor II | α-globin β-globin CFTR Glucocerebrosidase HFE Dystrophin Factor VIII Neurofibromin β-globin Factor V Prothrombin |
Splice junction mutations | β thalassemia Cystic fibrosis | β-globin CFTR |
Intragenic inversion | Hemophilia A | Factor VIII |
Partial or full gene deletion | α thalassemia β thalassemia AR spinal muscular atrophy (SMA) Duchenne/Becker muscular dystrophy Hemophilia A Neurofibromatosis, type 1 | α-globin β-globin SMN-telomeric Dystrophin Factor VIII Neurofibromin |
Partial or full gene duplication | Charcot-Marie Tooth disease, type 1A Duchenne/Becker muscular dystrophy | PMP22 Dystrophin |
Trinucleotide repeat | Dentatorubro-pallidoluysian atrophy Fragile X syndrome Friedreich’s ataxia Huntington disease Myotonic dystrophy Spinocerebellar ataxia, type 1 X-linked SMA (Kennedy’s disease) | Atrophin (CAG) FMR-1 (CGG) Frataxin (GAA) Huntingtin (CAG) Myotonin kinase (CTG) Ataxin (CAG) Androgen receptor(CAG) |
Hybrid genes d/t chromosomal crossover | β thalassemia | β and γ globin |
Imprinted genes | Prader-Willi syndrome (maternal) Angelman’s syndrome (paternal) Beckwith-Wiedmann syndrome |
Molecular biology of solid tumors
Associations between molecular changes and prognosis
Tumor | Alteration | Association |
Bladder cancer | LOH RB Genomic alterations 2q-, 5p+, 5q-, 6q-, 8p-, 10q-, 18q-, 20q+ | High grade/muscle invasion Higher grade |
Breast cancer | Plasma DNA similar to tumor DNA Allelic loss at 1p22-p31 | Poor prognosis Lymph node metastasis, tumor size > 2cm |
Cervical carcinoma | LOH on chromosome 1 | Advanced stage |
Colorectal cancer | LOH at 18q21 P53 expression MI and K-ras mutations P16-hypermethylation | Recurrence/poor survival Recurrence/poor survival Predictive of cancer Shorter survival |
Gastric cancer | LOH p53 LOH of 7q (D7S95) | Invasive potential Poor prognosis |
Gliomas | Chromosome 22q loss | Astrocytoma progression |
HNSCC | LOH of 14q LOH on 2q LOH at 17p | Poor outcome Poor prognosis Chemoresistance |
Melanoma | LOH in plasma | Advanced stage/progress |
Neuroblastoma | N-myc amplification TRK-A expression | Poor prognosis Good prognosis |
Neuroblastomas, 4s | N-myc amplification, 1p deletion 17q gains, elevated telomerase activity | Poor outcome |
NSCLC | Allelic imbalances on 9p Reduced Fhit protein expression LOH 11p13 | Poor Poor Poor |
PNET | LOH of 17p c-myc amplification | Metastatic Poor |
Prostate cancer | LOH on 13q | Advanced |
Retinoblastoma | LOH at RB1 locus |
HNSCC : head and neck squamous cell carcinoma
LOH : loss of heterozygosity
NSCLC : non-small cell lung cancer
PNET : primitive neuroectodermal tumor
Genes associated with inherited cancer syndromes
Condition | Genes | Classification |
Breast and/or Ovarian cancer | BRCA 1/2 | Tumor suppressor |
Familial adenomatous polyposis (FAP) | APC | Tumor suppressor |
Hereditary nonpolyposis colorectal cancer (HNPCC) | hMSH2, hMLH1 PMS1, PMS2 hMSH3, hMSH6 | Mismatch repair |
Renal cancer | VHL | Tumor suppressor |
Neurofibromatosis type 1/2 | NF1, NF2 | Tumor suppressor |
Nevoid basal cell carcinoma | PTC | Development and cellular proliferation |
Inherited prostate cancer | BRCA1, HPC1 | Tumor suppressor |
Familial melanoma | MLM1, CDKN2A CDK4 | Cell cycle regulator, oncogene (CDK4) |
Multiple endocrine neoplasia (MEN2A/B) | RET | Oncogene |
Li-Fraumeni syndrome | P53 | Tumor suppressor |
Tuberous sclerosis | TSC1, TSC2 | Tumor suppressor |
Retinoblastoma | RB1 | Tumor suppressor |
Rhabdoid predisposition | HSNF5/INI1 | Tumor suppressor |
Xeroderma pigmentosum | XP | DNA repair |
Bloom’s syndrome | BLM | Helicase (ligation) |
Ataxia telangiectasia | ATM | Cell cycle regulator |
Molecular biology of infectious diseases
Selected examples of microbes detected with the use of DNA probes and amplification techniques
Type | Examples |
Bacteria | Legionella spp. Group A streptococci |
‘Higher’ bacteria | Nocardia spp. |
Mycobacteria | Mycobacterium tuberculosis Mycobacterium avium Mycobacterium intracellulare |
Fastidious or noncultivable organisms | Coxiella burnetii |
Fungi | Aspergillus spp. Histoplasma capsulatum Blastomyces dermatitidis Pneumocystis carinii Cryptococcus neoformans |
Viruses | Herpes simplex Human immunodeficiency virus Human cytomegalovirus |
Parasites | Toxoplasma gondii |
Molecular biology of hematopoietic disorders
Common recurring chromosomal translocations in non-Hodgkin lymphoma
Disease | Translocation | Oncogene |
Small lymphocytic lymphoma Mantle cell Lymphoplasmacytic Marginal zone Follicle center cell Burkitt Diffuse large cell Anaplastic large cell | t(14;19)(q32;q13.1) t(11;14)(q13;q32) t(9;14)(p13;q32) t(11;18)(q21;q21) t(14;18)(q32;q31) t(8;14)(q24;q32) t(2;8)(q12;q24) t(8;22)(q24;q11) t(3;-)(q27;-) (t2;5)(q23;q35) | BLC-3 CCNDI (cyclin D1) PAX5 Unknown BCL-2 C-Myc C-Myc C-Myc BCL-6 NPM-ALK |
Common recurring chromosomal translocations encountered in acute leukemias
Disease | Translocation | Genes |
AML AML-M2 AML-M3 AML-M4Eo AML-M4/M5, biphenotypic AML-M5, biphenotypic CML Precursor B-ALL Pre-B-ALL B-ALL | t(6;9)(p23;q34) t(8;21)(q22;q22) t(15;17)(q22;q21) inv(16)(p13;q22) t(11;19)(q23;p13) t(9;11)(p21;q23) t(9;22)(q34;q11) t(12;21)(p13;q22) t(9;22)(q34;q11) t(4;11)(q21;q23) t(1;19)(q23;p13) t(8;14)(q24;q32) | DEK-CAN AML1-ETO PML-RARα CBFβ-MYH MLL-ENL MLL-AF9 BCR-ABL ETV6-AML1 BCR-ABL MLL-AF4 E2A-PBX1 MYC-IgH |
Human blood group systems
System name | Chromosome location | Gene products |
ABO Rh | 9q34.1-q34.2 1p36.13-p34 | A = α-N-acetylgalactosaminyl transferase B = α-galactosyl transferase RhD and RhCE, 30-32 kDa multipass polypeptides |
HLA : the major histocompatibility complex
Class I – HLA-A, HLA-B, and HLA-C
Class II – HLA-DP, HLA-DQ, HLA-DR
Class III – C2, C4, BF, TNF
Some prominent associations of disease with class I antigens
Disease | HLA | RR |
Idiopathic hemochromatosis Vitiligo Acute anterior uveitis Ankylosing spondylitis Reiter’s disease Duodenal ulcer Subacute thyroiditis Psoriasis vulgaris | A3 B35 B27 B27 B27 B35 B35 Cw6 | 6.77 13.9 10.4 87.4 37.0 2.7 13.7 13.3 |
Some prominent associations of diseases with class II antigens
Disease | HLA | RR |
Allergy Multiple sclerosis Narcolepsy Celiac disease Goodpasture’s disease Insulin dependent diabetes Systemic lupus erythematosus Rheumatoid arthritis Insulin dependent diabetes Pemphigus vulgaris Juvenile rheumatoid arthritis Pernicious anemia Nephrotic syndrome | DR2 DR2, DQ6 DQ6 DQ2 DR3 DQ8 DR3 DR4 DR4 DR4 DR8 DR5 DR7 | 19.0 4.1 >38 >250 15.0 14 2.6 9 15.4 14.4 8 5.4 5.9 |
