TYK2

Also known as

• Tyrosine kinase 2
  
• Non-receptor tyrosine-protein kinase TYK2 
• EC 2.7.10.2
• JTK1
  

 

Physiology

Activated by:

• IFNAR2
  
• Type I interferon signalling
• Type III interferon signalling
  
• IL-6 (Interleukin 6)
• IL-10 (Interleukin 10)
• IL-12 (Interleukin 12)
• IL-23 (Interleukin 23)

Molecular actions

1. IFNAR1 (subunit 1) and IFNAR2 (subunit 2) form a cell surface receptor called IFNAR (Interferon-alpha/beta receptor).
2. IFNAR1 associates with the enzyme TYK2. 
3. IFNAR2 associates with the enzyme JAK1.

Interferon signalling

1. IFNAR1 or IFNAR2 binds an IFN to form a binary complex.
2. The interferon-subunit complex recruits the other IFNAR subunit to form a ternary complex.

JAK/STAT signalling

1. JAK1 and TYK2 are brought into close proximity and phosphorylate the 2 IFNAR subunits.
2. IFNAR recruits proteins called STATs (Signal transducer and activator of transcriptions). The STATs are activated by phosphorylation.
   
3. pSTATs form homodimers (e.g. STAT1-STAT1) or heterodimers (e.g. STAT1-STAT2). 
4. pSTAT dimers enter the cell nucleus and bind to the DNA.
5. Transcription is blocked or reduced in some target genes (repression).
6. Transcription is activated in some target genes (expression).

 

Biological functions

• Immunity
  
• Antiviral responses
• Pro-inflammatory responses

 

Clinical significance

Disorders associated with TYK2 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
• Chronic hepatitis C infection
• Immunodeficiency 35 (IMD35)
• Hyperimmunoglobulin E syndrome (HIES)
• Lymphomatoid Papulosis
• Primary cutaneous anaplastic large cell lymphoma
• Polycythemia vera

These disorders suggest an increased susceptibility to severe infections and malignancies, possibly due to cytokine signalling deficiencies. 

 

Protein profile

• Size = 1187 amino acids
• Molecular mass = 133,650 Da
• Quaternary structure: Interacts with JAKMIP1. IFNAR1 interacts with TYK2. IFNAR2 interacts with JAK1.
• Protein family = Enzyme > Tyrosine kinase > Janus kinase

 

Genetic profile

• Species: Human
• Chromosome: 19
• Band: 19p13.2
• Starts at base pair: 10,350,529
• Ends at base pair: 10,380,572 
• Sequence length (base pairs): 30,043

 

See also

• genecards.org
  
• Interferon
  

IFNAR2

Also known as

• Interferon-alpha/beta receptor beta chain
• Interferon Alpha And Beta Receptor Subunit 2
• Interferon (Alpha, Beta And Omega) Receptor 2
• Type I Interferon Receptor 2
• IFNABR

 

Physiology

IFNAR2 is activated by:

• Type I interferons
  
1. IFN-α
2. IFN-β
3. IFN-ε
4. IFN-κ 
5. IFN-ω
• Type III interferons
1. IFN-λ1
2. IFN-λ2
3. IFN-λ3
4. IFN-λ4

 

Molecular actions

1. IFNAR1 (subunit 1) and IFNAR2 (subunit 2) form a cell surface receptor called IFNAR (Interferon-alpha/beta receptor).
2. IFNAR1 associates with the enzyme TYK2. 
3. IFNAR2 associates with the enzyme JAK1.

Interferon signalling

1. IFNAR1 or IFNAR2 binds an IFN to form a binary complex.
2. The interferon-subunit complex recruits the other IFNAR subunit to form a ternary complex.

JAK/STAT signalling

1. JAK1 and TYK2 are brought into close proximity and phosphorylate the 2 IFNAR subunits.
2. IFNAR recruits proteins called STATs (Signal transducer and activator of transcriptions). The STATs are activated by phosphorylation.
   
3. pSTATs form homodimers (e.g. STAT1-STAT1) or heterodimers (e.g. STAT1-STAT2). 
4. pSTAT dimers enter the cell nucleus and bind to the DNA.
5. Transcription is blocked or reduced in some target genes (repression).
6. Transcription is activated in some target genes (expression).

 

Biological functions

• Immunity
  
• Antiviral responses
• Pro-inflammatory responses
  

 

Clinical significance

Disorders associated with IFNAR2 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
• Measles as a result of MMR vaccination
  
• Severe HHV6 infection
  
• Immunodeficiency 45 (IMD45)

These disorders suggest an increased susceptibility to severe viral infections, possibly due to an interferon signalling deficiency.

 

Protein profile

• Size (amino acids) = 515
• Molecular mass (Daltons) = 57,75
• Quaternary structure: Heterodimer with IFNAR1. Isoform 1 interacts with the transcriptional factors STAT1 and STAT2. IFNAR1 interacts with TYK2. IFNAR2 interacts with JAK1.
• Protein family: Cell surface receptor.

 

Genetic profile

• Species: Human
• Chromosome: 21
• Band: 21q22.11
• Starts at base pair: 33,229,901
• Ends at base pair: 33,265,675
• Sequence length (base pairs): 35,775
  

 

See also

• genecards.org
• Interferon
  

CCR2

Also known as

• C-C Chemokine Receptor Type 2
• C-C Motif Chemokine Receptor 2  
• CD192
• Cluster of differentiation 192
  
• Monocyte Chemoattractant Protein 1 Receptor
• Monocyte Chemotactic Protein 1 Receptor
  

 

Biological functions

• Immunity
  
• Antiviral responses
• Pro-inflammatory responses

 

Clinical significance

Disorders associated with CCR2 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
  

 

Protein profile

• Size (amino acids) = 374
  
• Molecular mass (Daltons) =  41,915
• Quaternary structure: Interacts with ARRB1. Interacts (via extracellular N-terminal region) with beta-defensin DEFB106A/DEFB106B. Interacts with NUP85; the interaction is required for CCR2 clusters formation on the cell membrane and CCR2 signaling.
  
• Protein family = Cell surface receptor.

 

Genetic profile

• Species: Human
• Chromosome: 3
• Band: 3p21.31
• Starts at base pair: 46,353,734
• Ends at base pair: 46,360,928
• Sequence length (base pairs): 7195

 

See also

• Chemokines 
• genecards.org

OAS1

Also known as

• 2'-5'-oligoadenylate synthetase 1

 

Laconic summary

• OAS1 is an enzyme. It promotes RNA degradation, to suppress viral infection.

 

Physiology

Upstream events:

• Expression of the OAS1 protein is induced by interferon signalling.
  
• OAS1 is activated by double-stranded RNA.
  

 

Molecular actions

• Activation of enzymes called RNASELs (latent ribonucleases).

 

Downstream outcomes:

• Degradation of host RNA within the cell. (Unavoidable consequence).
• Degradation of viral RNA within the cell. (Antiviral defence).
• Suppression of host protein synthesis. (Unavoidable consequence).
  
• Suppression of viral protein synthesis. (Antiviral defence).
  
• Suppression of viral RNA replication. (Antiviral defence).

 

Biological functions

• Suppression of viral replication.
  

 

Clinical significance

Disorders associated with OAS1 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology 
• Herpes simplex infection
• Yellow fever
• Infantile-onset pulmonary alveolar proteinosis hypogammaglobulinaemia
• Pulmonary alveolar proteinosis with hypogammaglobulinaemia
• Microphthalmia with limb anomalies

 

Protein profile

• Size (amino acids) = 400
  
• Molecular mass (Daltons) = 46,029
  
• Quaternary structure: Monomer. Homotetramer.
• Protein family = Enzyme. 2'-5'-oligoadenylate synthase.

 

Genetic profile

• Species: Human
• Chromosome: 12
• Band: 12q24.13
• Starts at base pair: 112,906,783
• Ends at base pair: 112,933,222
  
• Sequence length (base pairs): 26,439

 

See also

• genecards.org
• Interferon
  

DPP9

Also known as

• Dipeptidyl peptidase 9
• Dipeptidyl Peptidase-Like Protein 9
  

 

Physiology

Biological functions

• Cell adhesion

 

Clinical significance

Disorders associated with DPP9 variants include:

• Coronavirus Disease 2019 (COVID-19)
• Pathophysiology
• Idiopathic pulmonary fibrosis
• Chronic nasopharyngitis 
  

 

Protein profile

• Size (amino acids) = 863
  
• Molecular mass (Daltons) = 98,263
  
• Quaternary structure: Homodimer.
  
• Protein family: Enzyme > Serine protease
  

 

Genetic profile

• Species: Human
• Chromosome: 7
• Band: 7q36.2
• Starts at base pair: 153,887,097
• Ends at base pair: 154,894,285
• Sequence length (base pairs): 49,450

 

See also

• genecards.org
• DPP4 (Dipeptidyl peptidase-4)

ACE2

Also known as

• Angiotensin-converting enzyme 2

 

Laconic summary

• ACE2 is an enzyme involved in RAAS. Several viruses exploit it to enter host cells.

 

Physiology

• Catalyses the conversion of angiotensin II (a vasoconstrictor) into 'angiotensin 1-7' (a vasodilator).
• Lowers blood pressure.

See: Renin-Angiotensin-Aldosterone system (RAAS).

• Renin
  
• Angiotensin
• Angiotensinogen
  
• Angiotensin I
• Angiotensin II
• Angiotensin (1-7)
• Angiotensin-converting enzyme
• Aldosterone
  

Clinical significance

Pathogenicity

Exploited to facilitate entry into host cells, by pathogens:

• SARS-CoV2
• Coronavirus Disease 2019 (COVID-19)
  
• Pathophysiology
• SARS-CoV
• Severe Acute Respiratory Syndrome (SARS)
• HCoV-NL63
  

Related genetic disorders:

• Hartnup disorder

Related medications:

• Angiotensin Converting Enzyme Inhibitors (ACE-Is)
  
• Angiotensin Receptor Blockers (ARBs)

ACE2 is upregulated in patients who take ACE-i / ARB therapies.

New therapeutics

• Recombinant ACE2 may be an effective therapeutic in the management of Acute Respiratory Distress Syndrome.

 

Protein profile

• Size (amino acids) = 805
  
• Molecular mass (Daltons) = 92,463
  
• Quaternary structure: Homodimer.
• Protein family = Enzyme > Metalloenzyme (zinc-containing)
  

 

Genetic profile

• Species: Human
• Chromosome: X
• Band: Xp22.2
• Starts at base pair: 15,561,033
• Ends at base pair: 15,602,148
• Sequence length (base pairs): 41,116

 

See also

• genecards.org

Pseudohypoparathyroidism

 Disease class: bone diseases, Metabolic
Disease class: Calcium metabolism disorders

Variants

• Pseudopseudohypoparathyroidism

 

See also

• Hyperparathyroidism
• Hypoparathyroidism

Friedreich ataxia

Disease class: Mitochondrial diseases

Disease class: Spinocerebellar degenerations

 

Haemoglobin C disease

Disease class: Haemoglobinopathies

Hereditary haemorrhagic telangiectasia

Disease class: Haemostatic disorders

Also known as

• HHT
• Osler-Weber-Rendu syndrome 

delta-Thalassemia

Disease class: Thalassaemia

Cysts

Disease class: Neoplasms

 

Hamartoma

Disease class: Neoplasms

Ataxia telangiectasia

Disease class: Immunologic deficiency syndromes

Disease class: Neurocutaneous syndromes

[Medical genetics] Introduction

Medical geneticists specialise in diseases of the karyotype and genotype of a patient.
There is significant overlap with paediatrics.
This is a pathology discipline.  

 

Etymology

Latin medicus, medica, medicum = healing, curative, medical
Ancient Greek γένεσις (génesis) = origin

 

Subspecialties

• Cytogenetics
• Molecular genetics

 

Responsibilities

• Counselling patients and their relatives about the implications of a diagnosis and the risks of inheritance
• Determining the type and number of chromosomes 
• Making prenatal diagnoses 
• Predicting the severity of disease from the genotype (e.g. counting gene duplications, microsatellite expansions, etc.)
• Sequencing a particular gene to identify mutations
• Screening for a known DNA sequence (e.g. known gene mutations)

 

Investigations 

• Deletion analysis  
• Dosage analysis 
• Linkage analysis   
• Methylation analysis 
• Microsatellite analysis

Screening for known mutations

• Comparative genomic hybridization (CGH) 
• Karyotype test
• Fluorescence in situ hybridization (FISH)

• Chemical cleavage of mismatch
• Multiplex ligation-dependent probe amplification (MLPA)
• Next generation sequencing (NGS) 
• Oligonucleotide ligation assay
• Polymerase chain reaction (PCR)
• Reverse Transcriptase-Polymerase chain reaction (RT-PCR)
• Southern blot analysis  

Identifying unknown mutations

• Comparative genomic hybridization (CGH) 
• Karyotype test

• Chemical cleavage of mismatch
• Denaturing Gradient Gel Electrophoresis (DGGE)
• Heteroduplex analysis
• Multiplex ligation-dependent probe amplification (MLPA) 
• Next generation sequencing (NGS) 
• Oligonucleotide ligation assay
• Protein truncation test
• Restriction fragment length polymorphism (RFLP)
• Reverse Transcriptase-Polymerase chain reaction (RT-PCR) 
• Single Strand Conformational Polymorphism (SSCP) 

 

History taking 

The history involves being able to construct an accurate and detailed family tree with all available information.

 

Physical examination

 The physical examination should be guided by both the presenting problems, and the suspected diagnoses. Many genetic diseases are strongly associated with a characteristic phenotype. A facies is a physical appearance which strongly points to a diagnosis.

 

Genetic diseases sorted by frequency

 

Inborn genetic diseases

Hyperoxaluria

Disease class: Kidney diseases

Inborn errors renal tubular transport

Disease class: Kidney diseases

Types

• acidosis, Renal tubular
• Bartter syndrome
• Dent diseas
• Fanconi syndrome
• Gitelman syndrome
• glycosuria, Renal
• hypophosphataemia, Familial
• Liddle syndrome
• Oculocerebrorenal syndrome
• Pseudohypoaldosteronism
• Renal aminoacidurias

Frasier syndrome

Disease class: Chronic kidney failure

Immunologic deficiency syndromes

Disease class: Immune system diseases

Types

• Agammaglobulinaemia
• Ataxia telangiectasia
• Common variable immunodeficiency
• Dysgammaglobulinaemia
• HIV infections
• Deltaretrovirus infections
• Leukocyte-adhesion deficiency syndrome
• Lymphopoenia
• Phagocyte bactericidal dysfunction
• Severe combined immunodeficiency 

This class includes all diseases caused by underactivity of the components of the immune system. 

Patients with these diseases have a significantly increased probability of severe or life-threatening infections. 

Nail-Patella syndrome

Disease class: Joint diseases