Because the rate of neurological problems is increased in children with CD, neurological abnormalities should be carefully investigated early after the diagnosis of CD is made.
Multisystem inflammatory syndrome in children (MIS-C) is a rare and severe condition that follows benign COVID-19. We report autosomal recessive deficiencies of
OAS1
,
OAS2
, or
RNASEL
in five unrelated children with MIS-C. The cytosolic dsRNA-sensing OAS1 and OAS2 generate 2′-5′-linked oligoadenylates (2-5A) that activate the ssRNA-degrading RNase L. Monocytic cell lines and primary myeloid cells with
OAS1
,
OAS2
, or
RNASEL
deficiencies produce excessive amounts of inflammatory cytokines upon dsRNA or SARS-CoV-2 stimulation. Exogenous 2-5A suppresses cytokine production in OAS1- but not RNase L-deficient cells. Cytokine production in RNase L-deficient cells is impaired by MDA5 or RIG-I deficiency and abolished by MAVS deficiency. Recessive OAS–RNase L deficiencies in these patients unleash the production of SARS-CoV-2–triggered, MAVS-mediated inflammatory cytokines by mononuclear phagocytes, thereby underlying MIS-C.
PARN, poly(A)‐specific ribonuclease, regulates the turnover of mRNAs and the maturation and stabilization of the h
TR
RNA component of telomerase. Biallelic
PARN
mutations were associated with Høyeraal–Hreidarsson (HH) syndrome, a rare telomere biology disorder that, because of its severity, is likely not exclusively due to h
TR
down‐regulation. Whether PARN deficiency was affecting the expression of telomere‐related genes was still unclear. Using cells from two unrelated HH individuals carrying novel
PARN
mutations and a human PARN knock‐out (KO) cell line with inducible
PARN
complementation, we found that PARN deficiency affects both telomere length and stability and down‐regulates the expression of
TRF1
,
TRF2
,
TPP1
,
RAP1
, and
POT1
shelterin transcripts. Down‐regulation of dyskerin‐encoding
DKC1
mRNA was also observed and found to result from p53 activation in PARN‐deficient cells. We further showed that PARN deficiency compromises ribosomal RNA biogenesis in patients' fibroblasts and cells from heterozygous
Parn
KO mice. Homozygous
Parn
KO however resulted in early embryonic lethality that was not overcome by
p53
KO. Our results refine our knowledge on the pleiotropic cellular consequences of PARN deficiency.
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