The 46,XX testicular DSD (disorder/difference of sexual development) and 46,XX ovotesticular DSD (46,XX TDSD and 46,XX OTDSD) phenotypes are caused by genetic rearrangements or point mutations resulting in imbalance between components of the two antagonistic, pro-testicular and pro-ovarian pathways; however, the genetic causes of 46,XX TDSD/OTDSD are not fully understood, and molecular diagnosis for many patients with the conditions is unavailable. Only recently few mutations in the WT1 (WT1 transcription factor; 11p13) gene were described in a group of 46,XX TDSD and 46,XX OTDSD individuals. The WT1 protein contains a DNA/RNA binding domain consisting of four zinc fingers (ZnF) and a three-amino acid (KTS) motif that is present or absent, as a result of alternative splicing, between ZnF3 and ZnF4 (±KTS isoforms). Here, we present a patient with 46,XX TDSD/OTDSD in whom whole exome sequencing revealed a heterozygous de novo WT1 c.1437A>G mutation within an alternative donor splice site which is used for −KTS WT1 isoform formation. So far, no mutation in this splice site has been identified in any patient group. We demonstrated that the mutation results in the retention of intron 9 in the mature mRNA of the 46,XX TDSD/OTDSD patient. In cases when the erroneous mRNA is translated, exclusively the expression of a truncated WT1 +KTS protein lacking ZnF4 and no −KTS protein occurs from the mutated allele of the patient. We discuss potential mechanisms and pathways which can be disturbed upon two conditions: Absence of Zn4F and altered +KTS/−KTS ratio.
Coronavirus disease (COVID-19), which was first recorded in China in December 2019, quickly spread to other countries and in a short period of time, the local outbreak escalated into a pandemic. There are significantly more cases of COVID-19 morbidity and mortality in European countries than in East Asia, where the disease was first detected. Such population differences are unique, especially for SARS-CoV-2 and are due to both socio-behavioral differences and features of the gene pool of the population of different countries. For infectious diseases, such as COVID-19, an important point is the genetic characteristics of individuals, which can determine its resistance or susceptibility to infection. Therefore, studies of the factors of hereditary predisposition to SARS-CoV-2 infection, as well as severity and mortality are extremely relevant. After genotyping among the healthy population of Ukraine and collecting relevant data from some European countries, we determined the correlation between morbidity, mortality from COVID-19 and the prevalence of genotype II (ACE1, I/D polymorphism) in the populations of Ukraine and several European countries. There was a negative correlation between the carrier of genotype II and susceptibility to SARS-CoV-2 infection per one million population (
R
= –0.53,
p
< 0.05), so individuals with genotype II can be considered more resistant to infection SARS-CoV-2. Further study of the role of allelic variants of the
ACE1
gene in the development of severity and complications affected patients of COVID-19, are promising for identified of genetic markers for development of personalized therapy.
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