Molecular disorders

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