ASSOCIATION OF VARIANTS IN THE CP, ATOX1
AND COMMD1 GENES WITH WILSON DISEASE
SYMPTOMS IN LATVIA
Zarina A1,2*, Tolmane I3,4, Krumina Z2, Tutane AI1, Gailite L1
*Corresponding Author: Ms. Agnese Zarina, Scientific Laboratory of Molecular Genetics, Rīga Stradiņš
University, 16 Dzirciema Street, Riga, Latvia, LV-1007. Tel.: +371-6706-1542. Fax: +371-67-471-815.
E-mail: agnese.zarina@rsu.lv or zarina.agnese@gmail.com
page: 37
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DISCUSSION
In our previous study, not all of the WD cases were
confirmed molecularly [15]. One explanation of undiagnosed
WD in a molecular level could be the fact that possibly
WD patients with clinically confirmed WD diagnosis
actually might have Wilson’s disease-like disease. Wilson’s
disease clinical and laboratory diagnostic criteria were developed
in 2001 and have not changed since. Several studies
have been published on the revision of the guidelines
and criteria [20] but remain unchanged at the European
level [11]. Two of the criteria for WD diagnostics are reduced
levels of ceruloplasmin in the blood and neurological
symptoms. In case of WD, the levels of ceru-loplasmin
are reduced due to copper accumulation, but other causes,
such as aceruloplasminemia and malabsorption, may also
cause reduced levels of ceruloplasmin [11]. Detection of
ceruloplasmin level in the blood is recommended as a first
step in WD diagnostics [21]. Very low levels of ceruloplasmin
in the blood (<5 mg/dL) are highly associated
with WD, but such low levels may also be found in other
diseases, e.g., aceruloplasminemia caused by pathogenic
allelic variants in the CP gene. Neurological symptoms of
aceruloplasminemia can mimic WD, but this is actually
due to the accumulation of iron [20]. In such cases, to
confirm aceruloplasminemia, serum ceruloplasmin levels
of first-degree relatives should be checked (serum ceruloplasmin
is also reduced in heterozygous patients with
pathogenic allelic variants), as well as patients with aceruloplasminemia
generally found to have reduced serum
iron levels, increased ferritin levels, diabetes and evidence
of iron accumulation in magnetic resonance imaging in the
brain [22]. In view of lack of the aforementioned changes
in symptoms and laboratory parameters in WD patients
without a molecularly confirmed diagnosis, the diagnosis
of aceruloplasminemia is questionable. The association
of allelic variants in the CP gene and different diseases
are described in various studies: with Parkinson’s disease
[8] and AFib [9,10], concluding that changes in the CP
gene promoter may be associated with altered levels of
ceruloplasmin. Analyzing the CP gene promoter in the
current study, it was concluded, that the AA genotype of the
rs66508328 variant and the GG genotype of rs11708215
(both according to the recessive inheritance model) were
more common in patients who were not confirmed molecularly
to have WD according to the ATP7B genotype.
This may indicate that the above-mentioned variants in
the CP gene could affect gene expression, resulting in
reduced levels of ceruloplasmin in the blood, that in turn,
leads to increased accumulation of iron in the brain, causing
Parkinson’s disease-like symptoms, which are also
characteristic of WD. The results observed here points to
a further development of the study by increasing the size
of the patient group, and although the differences were
statistically significant, due to the small size of the groups,
the data could have been accidental.
Considering the important interaction of ATOX1 protein
with ATP7B protein, there have been several studies
looking for possible changes in the ATOX1 gene in WD patients, but so far, the results have been negative [5,1]. In
this study, there were no identified changes in the ATOX1
gene causing functional changes of the protein, so we were
unable to prove that changes in the ATOX1 gene could
modify the WD phenotype.
In studies of changes in other genes that could affect
the clinical manifestations of WD, the researchers focused
on the COMMD1 gene, in which pathogenic variants have
been shown to cause copper toxicosis in Bedlington terriers
that is clinically similar to WD in humans [23]. There have
been several studies analyzing the possible effects of this
gene variants on humans. Stuehler et al. [24] revealed that
the substitution of the nucleotide in the position c.492T>C
(p.Asn164 or rs9096) is associated with earlier (about 10
years) expression of clinical symptoms in WD patients. In
this study, the above-described variant was also found in
Latvian patients. Analyzing its possible association with
clinical manifestations of the disease, the relationship was
not found, so the above observation was not confirmed. In
another study in 2010, Gupta et al. [6] reported the effect of
another variant, c.521C>T (p.Thr 174Met; rs139775239),
on the WD phenotype; they associate this variant with
more elevated levels of copper in the urine, as well as with
enhanced cell apoptosis in WD patients. In the current
study, no such variant was found in the COMMD1 gene
in any of the Latvian patients. There have been several
studies with the effect of COMMD1 gene variants on WD,
but unfortunately, no association with these studies was
confirmed [25,26], the same as in present study.
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