Ciliopathies - Tran Flashcards
What are the two types of cilia? Where are they found (and # found) and what is their primary function?
Motile cilia: function = beat; found in: brain ventricles, embryonic node, respiratory tract, sperm and female reproductive tract; varies but mostly more than one per cell
Non-motile primary cilia: function = signal; found in almost all vertebrate cells; one per cell
What was first found in algae? What is so important about this process?
Intraflagellar transport (IFT); builds and maintains cilia…allows for protein movement up and down the cilia
How are primary and motile cilia differentiated structurally?
primary: “9+0”…have the doublet microtubules only
motile: “9+2”…have outer dynein arms (ODA), inner dynein arms (IDA), radial spokes, and central microtubule pair
What is associated with anterograde and retrograde transport?
anterograde: Kinesin and IFT complex B
retrograde: Dynein and IFT complex A
What is the structure of primary cilia?
basal body: mother + daughter centriole
transition zone: gatekeeper
axoneme: main part of cilia that extends out from cell
What are the proteins associated the transition zone?
ciliary gate: MKS, NPHP
BBSome: required to shuttle ciliary proteins from Golgi to base of transition zone
Disruption of AAA causes ciliary structural defects due to BBB. Describe each type of AAA and how this would look under EM.
AAA: IFT components
BBB: defective protein trafficking
no IFT-B: no cilia
no IFT-A: as you go toward the tip of the cilia, the axoneme becomes more congested with proteins - appears oval
no dynein: more severe that IFT-A; cilia are short and a round bud (filled with proteins) will form
What are signals the Primary Cilium receive and receptors on the Primary Cilium?
signals: flow/movement, morphogens, light, chemical signals, growth factors
receptors: PC2, PC1, Ca+2, Patched, Frizzled, GPCR, PDGF-alpha
What provides motility?
dynein arms and central microtubule pair
What do primary cilia extend from and what does this affect?
extend from a modified centriole - influences the cell cycle
What is the only motile ciliopathy? What are some fo the most common clinical features?
primary ciliary dyskinesia (PCD) - can have a range of severity
clinical features: hydrocephalus, respiratory abnormalities, laterality defects (situs inversus), congenital heart defects, infertility
What causes PCD?
any gene mutation that affects: nexin-dynein regulatory complex, outer dynein arm, inner dynein arm, central pair of microtubules or radial spoke
What are the most common non-motile ciliopathies?
Bardet-Biedl Syndrome (BBS) - obesity, retinal degenration
Meckel Syndrome (MKS) - clinical triad: anencephaly, polydactyly, renal cystic dysplasia
Nephronophthisis (NPHP) - fibrorenal cystic disease with corticomedullary cysts
Joubert Syndrome (JBTS) - molar tooth sign (cerebellar defect)
Jeune Syndrome (JS) - skeletal defect: narrowed rib cage, shortened fingers and toes
Ellis-van Creveld Syndrome (EVC) - skeletal defect: dwarfism
PKD
Von Hippel Lindau Syndrome (VHL)
What are the most common features of non-motile ciliopathies? How do you know if it is not a non-motile cilipathy?
clinical signs that are NOT non-motile ciliopathies: infertility, respiratory anomalies
clinical signs that ARE non-motile cilipathies: cerebellum, obesity, skeletal deformations, renal cysts, and thoracic skeleton
Describe the genetics of non-motile ciliopathies.
typically autosomal recessive, however there was a case of triallelic inheriatance in BBS (Bardet-biedl syndrome); many genes are involved
What are two ciliary diseases that present with obesity? How?
Bardet-Biedl syndrome (BBS) and Alstrom Syndrome
cilia in the brain are affected - signaling pathways that correlate with eating are messed up and these individuals are always hungry
What causes PKD?
ARPKD: mutation in PKHD1 (1/20,000 children)…FPC protein cannot get to membrane
ADPKD: mutation in PKD1 (85%), PKD2 (15%) (1/500 adults)…PC1 and PC2 (from PKD1/2) cannot get to the membrane in the axonome of the cilia
Note: all tubular epithelial cells contain one mutated and one unaffected PKD1 or PKD2 allele; the other allele can mutate or over time the kidneys will mature and the cysts will increase in size…think of the two-hit hypothesis or the 3-hit hypothesis
What are the major cellular abnormalities of PKD?
increased cell proliferation and increased fluid secretion
What are the major factors affecting ADPKD progression?
age (younger diagnosis = worse outcomes) genotype (truncating PKD1) sex (male) race (African-Americans, Asians) hypertension gross hematuria environmental (water intake, caffeine consumption) other genes
What does PC deficiency lead to?
decreased intracellular calcium levels, which causes an area of abnormal cell proliferation which then causes continued cell proliferation and fluid secretion into the cysts
decreased Ca leads to an abnormal response to cAMP
explain the role of cAMP, Ca and normal/PKD kidney cells
ADPKD cells: intracellular cAMP levels are elevated and causes increased proliferation of ADPKD cells
cAMP -> PKA -> Ras -> Braf (inhibited by Ca) -> MEK -> ERK -> cell proliferation
in normal cells, PKA will not affect Ras…will actually inhibit Raf-1 which then is not able to stimulate MEK and thus prevents cell proliferation
describe fluid secretion in relation to PKD
vasopressin (anti-diuretic) stimulates cAMP which then acts on CFTR to increase amount of water in the cysts (Cl- goes from blood to cyst cells via NKCC1 and then from cyst cells to inside of cyst via CFTR…causes water to follow)
what is the only therapeutic drug for PKD? how does it function?
tolvaptan; competitive inhibitor of vasopressin receptor….leads to the decreased production of cAMP
patients are VERY thirsty because the anti-diuretic is being inhibited - do not retain water very well
not as effective in humans as mice - PKD is a multifactorial disease
what are the ciliopathies that are predisposing to cancer? How do they arise?
Von Hippel Lindau (VHL) and Birt Hogg Dube
these gene products do not localize to primary cilium
When are the two main times that cilia defects occur? what are the mechanisms that are being disrupted and what is the severity of the resulting disease?
- during morphogenesis: cilia defect occurs early in life which leads to problems with signaling and causes severe disease
- during tissue maintenance: cilia defect occurs later in life which leads to problems with cell proliferation and differentiation - tend to be less severe diseases
