The optimal sequence for caspase-1 is WEHDS/G at positions P4-P3-P2-P1-P1’, respectively, but the cleavage sequence in aSyn is VDPDN; thus, it is not optimal for efficient cleavage.

{Poreba, 2013 #2480} FIG3. The convention in naming substrate residues in protease active sites is to name the residue to the amino terminal of the scissile bond (arrow) P1 and the one to the carboxy-terminal side P1’.

All caspases show exquisite selectivity for Asp in the P1 position, a preference for Glu in P3

WEHD tetrapeptide was better than the YVAD tetrapeptide

Good review: Dharni 2021

CAPS

Questions

CSF in kid?
Samples postmortem?

Classification

Cryopyrin-Associated Periodic Syndromes (CAPS) (=cryopyrinopathies)

1/360,000 in France https://www.orpha.net/consor/cgi-bin/OC_Exp.php?Lng=GB&Expert=1451 2억명중 500명, 2 to 5 per million

	Familial Cold Autoinflammatory Syndrome (FCAS), (=familial cold-induced urticaria)	Muckle-Wells Syndrome (MWS)	Chronic Infantile Neurologic Cutaneous Articular syndrome (CINCA) (=Neonatal Onset Multi-systemic Inflammatory Disease (NOMID))
-overlap; a patient might be classified into a different group depending on the individual clinician's assessment, -phenotype can change over time, and - may also be considerably influenced by effective treatments with anti-IL-1 drugs.
Severity	Most mild	intermediate	Most severe
prevalence	(kim 2018) 22% in clinic No cns sx [Recurrent] exposure to generalized cold→ (7h후) in a stereotyped systemic inflammatory response including fever, an urticarial rash, conjunctivis, and substantial arthralgias, ↑ WBC, → resolve in 24h	(kim 2018) 22% in clinic No cns sx [Chronic] [triad] (heat and cold) → Intermittent episodes of fever, headache, urticarial rash, and joint pain (arthralgias or arthritis) 2. (Progressive) sensorineural hearing loss 3. (Secondary, adult) (AA) amyloidosis with nephropathy	(kim 2018) 55% in clinic 25% of CAPS Fever is rare
onset	Neonatal period	sensorineural hearing loss: childhood	within the first hours/days of life
Onset	(Levy, 2014 #1823) Eurofever registry (136 CAPS patients): 0.8 y (0.1-5)
Dx age	(Levy, 2014 #1823) 15 (5-36) y
Dx age	(Kim, 2018 #1822) 5y
	(Levy, 2014 #1823) Eurofever registry (136 CAPS patients) Recurrent 43% 이들은 ~15(?)빈/y, 2일정도 지속되는, cold-triggered, 열동반 attack 경험 Chronic w exacerbations 18% chronic 39%
Interval cycle	(some) daily Resolve in 24h	Every few weeks Lasting 12-36h
histology	Neurotrophil infiltration	Amyloidosis (tissue biopsy)	amyloidosis
prognosis	Good. quality of life can be affected by recurrent episodes of feve	long-term prognosis may be affected by amyloidosis and impaired renal function. Deafness is also a significant long-term complication.	Premature death may be possible,

Genetics

a. LocationL 1q44, Phenotype MIM number: 607115, Gene/LocusGene MIM number: 3606416

170 varants , Almost all the NLRP3 mutations so far identified have been observed within the exon 3, which is responsible for encoding the NACHT domain, crucial for cryopyrin oligomerization.

However, although patients with FCAS and MWS tend to show familial inheritance patterns, CINCA/NOMiD syndrome usually occurs de novo, and approximately 50–65% the patients with a CINCA/NOMiD phenotype lack detectable mutations in the NLRP3 coding region [13–16]. It has been suggested that different genes or a modifier gene could be involved in these latter cases, although they do not differ clinically from those carrying NLRP3 mutations. In the past few years somatic NLRP3 mosaicism rather than heterozygous germ-line mutation has been detected in up to 69.2% [17] of patients presenting symptoms typical of CINCA/NOMiD [17–22]. Thus, for a majority of genetically negative CINCA/NOMiD patients, the disease onset may be caused by low-level mosaicism in the absence of detectable NLRP3 gene mutations by ordinary genomic sequencing [18–20]. NLRP3 mosaicism is thus an established major cause of CINCA/NOMID [17]. However, only recently, insights regarding the relevance of this mechanism were provided in other CAPS phenotypes [23, 24]. Namely, a variable degree (5.5–34.9%) of somatic NLRP3 mosaicism vertical transmission was detected in patients with a MwS phenotype, pointing at somatic NLRP3 mosaicism as shared genetic mechanism in the whole CAPS spectrum, not restricted to CINCA/NOMiD clinical picture [23, 24]. low-penetrance NALP3 variants (Q703K, R488K, V198M) may present atypically

(Levy, 2014 #1823) Eurofever registry (136 CAPS patients)

• 31 (all missense mutation) different NLRP3 mutations were recorded; (all but L1016F were located in exon 3 of NLRP3.), 대개 heterozygous
  • 7 accounted for 78% of the patients,
  • whereas 24 rare variants were found in 27 cases.
  • R260W>T348M>A439V,V198M>E311K,Q703K>D303N

Figure 1 Genotype distribution among the cryopyrin-associated periodic syndrome patients. Distribution of NLRP3 mutations in the cohort of 136 patients.

• pie chart legend: No mutation, R260W, T348M, D303N, A439V, E311K, V198M, Q703K, Other mutations
• pie slice labels (visible): 20%, 26%, 15%, 4%, 10%, 7%, 10%, 7%, with a small “2%” tag near the 7% slice

family Hx: yes 55.8% vs no 39.7%

[(Houx, 2015 #1835)] large French database: R260W (34%) > A439V (20%) > T348M (16%) > D303N (4%), The four accounted for 73% of the patients

[Genotype-phenotype correlation] Good in Levy, 2014 #1823) Eurofever registry (136 CAPS patients), patients bearing a rare variant of NLRP3 presented with a more severe phenotype,

Inheritance

• b. autosomal dominant. Affected patients carrying a germinal mutation have a 50% risk of transmitting the disease to each child.
• c. In case of somatic mosaicism, risk depends on the possible presence of somatic mutations in reproductive organs of the parents.
• d. LocationL 1q44, Phenotype MIM number: 607115, Gene/LocusGene MIM number: 3606416
• e.

MOA

oF point mutations in NLRP3 gene	↑ cryopyrin (?)	NLRP3 activation (formation)		systemic: ↑ IL-1, IL-6, and TNF-α.	(liver) 아마 IL-1b가 hepatocyte에 있는 IL-1R에 붙나? The combination of IL-6) and IL-1) synergistically induces CRP) in Hep3B cells→ ↑ CRP, ↑ SAA
					IL-1 binds IL-1R→ ↑ Neurotrophil (아마 lymphocyte (T cell)도)

IL-1β

		N			Stimulation?
{Mann, ?? #1832}	FCAS/MWS	9?	In vivo	Production (into plasma?)	x		Healthy controls were estimated to produce about 6 ng/dL of IL-1β, and patients with FCAS/MWS about 31 ng/dL These levels are even higher in NOMID/CINCA patients).
{??, 2004}	CINCA	1	Ex vivo	Blood cell (whole blood)	LPS	ELISA

Uncertain Spans

location	transcription	uncertainty
Genetics intro	170 varants	”varants” is the source spelling and appears intentional; could read 170 variants but the source typography matches “varants”.
Recurrent / Chronic table	이들은 ~15(?)빈/y, 2일정도 지속되는, cold-triggered, 열동반 attack 경험	The numeric inside parens after ~15 is partly hidden by a fold; reading is uncertain.
IL-1β table {Mann, ?? #1832}	{Mann, ?? #1832}	The four-digit year is too small to read between the author and the citation key.