please write a literature review like a following"Discussion
Here, we report an IHPRF1 patient with a homozygous
mutation c.2563C>T p.R855X in the NALCN gene. The
wild type NALCN protein contains four homologous repeats,
each of which comprises six transmembrane segments with
the pore-forming region of each domain located between the
fifth and the sixth transmembrane segments.3 Due to the
truncating effect of the mutation, loss of 884 out of 1738
amino acids of the wild type protein is predicted. Hence, the
resulting protein would contain only two out of the four
above-mentioned domains (Figure 1).
Although the same mutation was previously described in
a compound heterozygote individual (pat: p.R855X, mat: p.
R1094Q),19 there are no previous publications of this mutation
in the homozygous form. Hence, the current report provides
the first description of the direct effects of this truncating
homozygous mutation. Interestingly, the patient described by
Campbell et al (2018) is probably the least affected individual
among all the reported IHPRF1 patients, so far. They suggested
that the milder manifestation of the disease phenotypes might
Figure 1 (A) Patient’s dysmorphic phenotypes. Pectus carinatum, severe muscle atrophy, pes varus, and scoliosis are evident. (B) Patient’s pedigree along with the results of
Sanger sequencing for the respective individuals. All tested individuals, except for the proband, were revealed to be heterozygote for the detected mutation in the NALCN
gene. (C) The NALCN protein structure. This protein consists of four transmembrane domains (shown by D1 to D4), each of which contains six transmembrane segments.
Twenty-one of the described missense, frameshift, and nonsense mutations are marked with green, orange, and red, respectively. The homozygous nonsense mutation
detected in our patient (Arg855Ter) (distinguished by an ellipse) is located on the cytoplasmic loop, between the second and the third transmembrane domains. The
hypothetical truncating effect of this mutation on the protein is illustrated.
Karimi et al Dovepress
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154 The Application of Clinical Genetics 2020:13 
be due to the fact that the missense mutation of the compound
heterozygote patient is located on the third transmembrane
domain of the NALCN protein. However, it is noteworthy
that a missense mutation in the fourth transmembrane domain
of the NALCN also resulted in a milder manifestation of the
disease.20 Moreover, there are reports of several truncating
mutations located both in and after the third transmembrane
domain of the NALCN protein, which resulted in much more
severe manifestations of the disease.20–22 Considering these,
the exhibition of milder clinical symptoms in the patients
reported by Campbell et al (2018), the patients in the family
2 described by Al-Sayed et al (2013), and individuals 16 and 17
described by Bramswig et al (2018) might also be attributed to
the missense nature of the mutation. Three points, however,
should be taken into account: First, hypothetically, mRNAs
produced from the mutated genes with stop gain mutations can
undergo nonsense-mediated decay (NMD), thus, the more
severe exhibition of the disease phenotypes in patients with
stop gain mutations in or after the third transmembrane domain
of the NALCN might be due to the general downregulation of
the truncated protein by this mechanism. Second, to the best of
our knowledge, there are only four reported missense mutations in the NALCN gene which are all located in the third and
the fourth transmembrane domains of NALCN protein (Figure
1).19,20,23 Third, in a recent study, no sodium background
current was detected in cells expressing p.Trp1287Leu missense mutation which might suggest underlying factors other
than residual channel activity for the milder exhibition of the
symptoms in the individuals affected by this mutation.10 With
that being said, further accumulation of the IHPRF1 reports
can help in the delineation of this matter. Beyond any doubt,
rapid progress in the field of next-generation sequencing
allows for a more accurate and less expensive diagnosis and
study of genetic defects.24–26
Considering the extremely high rate of constipation in
all the IHPRF1 patients reported so far (present in 31 out
of 34 examined individuals), constipation can be considered as one of the most prominent symptoms of this
disease, along with global developmental delay and dysmorphic features (for a summary of the symptoms manifested in all the 36 patients reported so far, please see the
Supplementary table). Cardiovascular malformation, however, is seldom associated with IHPRF1. To the best of our
knowledge, other than the current case, there is only one
other reported individual diagnosed with ASD,27 and there
is no previous report of TR in IHPRF1 patients.
The patient described in this report had an older male
sibling with similar phenotypes who passed away genetically
undiagnosed at the age of 3.5 months. Interestingly, the male
sibling also exhibited seizures which is a common phenotype
in IHPRF1 patients (present in more than 47% of the
described individuals). This made us suspect that sex might
play a role in the extent of the disease severity. We specifically compared the disease status in all the seven oppositesex IHPRF1 siblings described in the previous
reports.19,20,22,28,29 Our interpretation of the information provided by the authors in their respective manuscripts is that
there seems to be a bias towards the more severe exhibition
of the IHPRF1 phenotypes in the male individuals. In two of
the described siblings (individuals 2 and 3, and individuals 11
and 12 described by Bramswig et al (2018)), we were not
able to identify any major difference between the individuals.
In all the other siblings described, the male individuals seem
to present a more severe phenotype compared to their female
siblings. Although the number of reported siblings is not
enough to draw conclusions, we suggest that the sex of the
affected individual might have an influence on the extent to
which IHPRF1 phenotypes manifest. In agreement with this
hypothesis, the study of the effects of estrogen and progesterone hormones on the regulation of the NALCN expression
in human myometrial smooth muscle cells suggests a sexdependent biology for the NALCN.30
NALCN has been identified as a cation channel involved in
the conductance of substance P-activated cation channel
current.4 Considering that it has been shown that SP plays
important roles in a wide variety of physiological processes
including cardiovascular system activity, cell growth and proliferation, inflammation, pain sensation, respiration, and pacemaking activity in the gastrointestinal tract,31–33 some of the
phenotypes associated with IHPRF1 disease can be attributed
to the disability of the mutated NALCN in the conductance of
the SP-activated cation channel current. Indeed, it has been
shown that NALCN is an important component in the SPmediated modulation of gastrointestinal motility through interstitial cells of Cajal and also is essential in respiratory system
response to SP.
34,35 Furthermore, the study of IHPRF1 from
the perspective of the other known regulators of the NALCN
channelosome, namely neurotensin, acetylcholine, GABA,
extracellular calcium, and dopamine, would be essential for
a better understanding of this disorder"