4. Discussion
MuSKis located in Cytogenetic
location:9q31.3,
Genomic coordinates(GRCh38): chr9:110,668,188-110,806,632.
A mutation in MuSK associated with autosomal recessive FADS was
firstly reported in 2015, which presented a family trio in inheritance
mode with an insertion mutation in exon 1 of MuSK . It resulted in
prematurely terminate translation [Wilbe et al.,2015]. MuSK is a
receptor tyrosine kinase expressed on the muscle cell membrane
[DeChiara et al.,1996; Glass et al.,1996].
Acetylcholine(ACh)
is a medium for signal transmission. The combination of ACh and
acetylcholine receptors (AChR) can cause muscle contractions. MuSK is a
component of the AChR pathway and a major regulator of neuromuscular
connection formation and maintenance[Wilbe
et
al.,2015]. The mutation of MuSK gene can lead to the decreased
expression of mRNA level and stability of Musk protein level. When AChR
was decreased, it led to muscle contractility disorder. Up to December
31, 2019, four families with 24 patients with FADS had been reported
carrying MuSK mutation(Table1). Two families carried homozygous
mutations, and one carried a compound heterozygous mutation [Wilbe et
al.,2015; Tan-Sindhunata et al.,2015; Li et al.,2019]. Of the 24
patients, 45.8% (11/24) selected termination of pregnancy, 4.1%(1/24)
developed intrauterine fetal death, one was stillborn, and 45.8%
(11/24) died after birth. The longest survival time was five days. No
survival cases were reported. These pregnancy outcomes were consistent
with previous studies. Wible et al. knocked out the Mouse MuSKgene and conducted animal experiments. They identified that loss of
function mutations occur in MuSK is lethal. In this case, the
nonsense mutation(NM-005592.3) c.790C > T is expected to
cause the encoded protein to truncate and lose its normal function. The
missense mutation (NM-005592.3) c.296G >T is expected to
change the amino acid at position 99 of the encoded protein from Cys to
Phe. Various bioinformatics tools predict this amino acid change with
potential pathogenic effects. MuSK has an important biological
function, and it is highly conserved across most species. MuSK protein
contains IgG-like domains, extracellular domain,Frizzled-like
cysteine-rich domain,atransmembrane domain and a cytoplasmic
domain[Stiegler et al.,2009]. In this case, the two mutations
located in Ig-like1/3 in an extracellular domain. The extracellular
domain of MuSK plays an important role in AChR cluster, which can lead
to muscle contractility disorder. Based on the fetus’ ultrasound
examination, we identified the two mutations are pathogenic variation.
The fetal ultrasound manifestations of the previous twice pregnancies of
this patient were very similar to this one, so we speculated that the
previous twice fetuses perhaps carried the same pathogenic MuSKgene.