Genetic variation spectrum in <i><scp>ATP</scp>7B</i> gene identified in Latvian patients with Wilson disease

Zariņa, Agnese; Tolmane, Ieva; Kreile, Madara; Chernushenko, A.; Cernevska, Gunta; Puķīte, Ieva; Mičule, Ieva; Krūmiņa, Zita; Krūmiņa, Astrīda; Rozentāle, Baiba; Piekuse, Linda

doi:10.1002/mgg3.297

Cited by 5 publications

(5 citation statements)

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“…However, in Korea, where WD is one of the most common inherited metabolic disorders, the carrier frequency and incidence of WD are estimated to be 1 in 88.2 and 1 in 30,778, respectively [ 4 ]. In Latvia, the estimated prevalence of WD is 1 in 24,000 cases [ 5 ]. Screening of WD in the UK population suggests that the frequency of individuals predicted to carry two mutant pathogenic ATP alleles is 1 in 7026, which is considerably higher than the typically reported prevalence [ 6 ].…”

Section: Introductionmentioning

confidence: 99%

Mutation analysis of the ATP7B gene and genotype–phenotype correlation in Chinese patients with Wilson disease

Wen-long

et al. 2021

BMC Gastroenterol

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Aim To discover the novel ATP7B mutations in 103 southern Chinese patients with Wilson disease (WD), and to determine the spectrum and frequency of mutations in the ATP7B gene and genotype–phenotype correlation in a large-scale sample of Chinese WD patients. Methods One hundred three WD patients from 101 unrelated families in southern China were enrolled in this study. Genomic DNA was extracted from the peripheral blood. Direct sequencing of all 21 exons within ATP7B was performed. Subsequently, an extensive study of the overall spectrum and frequency of ATP7B mutations and genotype–phenotype correlation was performed in all Chinese patients eligible from the literature, combined with the current southern group. Results In 103 patients with WD, we identified 48 different mutations (42 missense mutations, 4 nonsense mutations and 2 frameshifts). Of these, 3 mutations had not been previously reported: c.1510_1511insA, c.2233C>A (p.Leu745Met) and c.3824T>C (p.Leu1275Ser). The c.2333G>T (p.Arg778 Leu) at exon 8, was the most common mutation with an allelic frequency of 18.8%, followed by c.2975C>T (p.Pro992Leu) at exon 13, with an allelic frequency of 13.4%. In the comprehensive study, 233 distinct mutations were identified, including 154 missense mutations, 23 nonsense mutations and 56 frameshifts. Eighty-five variants were identified as novel mutations. The c.2333G>T (p.Arg778 Leu) and c.2975C>T (p.Pro992Leu) were the most common mutations, with allelic frequencies of 28.6% and 13.0%, respectively. Exons 8, 12, 13, 16 and 18 were recognised as hotspot exons. Phenotype–genotype correlation analysis suggested that c.2333G>T (p.Arg778 Leu) was significantly associated with lower levels of serum ceruloplasmin (P = 0.034). c.2975C>T (p.Pro992Leu) was correlated with earlier age of disease onset (P = 0.002). Additionally, we found that the c.3809A>G (p.Asn1270Ser) mutation significantly indicated younger onset age (P = 0.012), and the c.3884C>T (p.Ala1295Val) mutation at exon 18 was significantly associated with hepatic presentation (P = 0.048). Moreover, the patients with mixed presentation displayed the initial WD features at an older onset age than the groups with either liver disease or neurological presentation (P = 0.039, P = 0.015, respectively). No significant difference was observed in the presence of KF rings among the three groups with different clinical manifestations. Conclusion In this study, we identified three novel mutations in 103 WD patients from the southern part of China, which could enrich the previously established mutational spectrum of the ATP7B gene. Moreover, we tapped into a large-scale study of a Chinese WD cohort to characterise the overall phenotypic and genotypic spectra and assess the association between genotype and phenotype, which enhances the current knowledge about the population genetics of WD in China.

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Section: Introductionmentioning

confidence: 99%

Mutation analysis of the ATP7B gene and genotype–phenotype correlation in Chinese patients with Wilson disease

Wen-long

et al. 2021

BMC Gastroenterol

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“…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.…”

Section: Discussionmentioning

confidence: 78%

“…Direct DNA sequencing of the ATP7B gene (promoter, exons and exon-intron boundaries) was performed for the patients with WD symptoms, being either heterozygous for H1069Q or without it on any allele. Methods for WD molecular confirmation and the group of WD patients have been described before in detail [14,15].…”

Section: Methodsmentioning

confidence: 99%

Association of variants in the CP, ATOX1 and COMMD1 genes with Wilson disease symptoms in Latvia

Zariņa

Tolmane

Krūmiņa

et al. 2019

Balkan Journal of Medical Genetics

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Wilson’s disease (WD) is a copper metabolism disorder, caused by allelic variants in the ATP7B gene. Wilson’s disease can be diagnosed by clinical symptoms, increased copper and decreased cerulopasmin levels, which could all also be by other genetic variants beyond the ATP7B gene, e.g., disturbed ceruloplasmin biosynthesis can be caused by pathogenic allelic variants of the CP gene. Copper metabolism in the organism is affected by several molecules, but pathogenic variants and related phenotypes are described with COMMD1 and ATOX1 genes. The aim of the study was to test other genes, CP, ATOX1 and COMMD1, for possible influence to the manifestation of WD. Patients were enrolled on the basis of Leipzig’s diagnostic criteria, 64 unrelated patients with confirmed WD. Direct sequencing of promoter region of the CP gene and ATOX1 and COMMD1 gene exons was conducted. Statistically significant differences were found between the two variants in the CP gene and the ATP7B genotype (rs66508328 variant AA genotype and the rs11708215 variant GG genotype) were more common in WD patients with an unconfirmed ATP7B genotype. One allelic (intronic) variant was found in the ATOX1 gene without causing the functional changes of the gene. Three allelic variants were identified in the COMMD1 gene. No statistically significant differences were found between allele and genotype frequencies and the first clinical manifestations of WD. Different variants of the CP gene contributed to a WD-like phenotype in clinically confirmed WD patients with neurological symptoms and without identified pathogenic variants in the ATP7B gene. Allelic variants in the ATOX1 and COMMD1 genes do not modify the clinical manifestation of WD in Latvian patients. (266 words)

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“…The clinical manifestations of this mutation primarily involve extrahepatic symptoms such as tremor, dystonia, and mental symptoms. [ 13 ] In Asian populations, the most common mutation type is the Arg778Leu missense mutation in exon 8, which is most prevalent in China, South Korea, and Japan, with an allele frequency of 17.3% to 60%. The clinical symptoms associated with this mutation are predominantly liver damage, such as liver dysfunction and liver cirrhosis.…”

Section: Discussionmentioning

confidence: 99%

A novel mutation in the ATP7B gene causing hepatolenticular degeneration in a Chinese family: A case report

Zhou,

Zhang,

et al. 2024

Medicine

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Introduction: Hepatolenticular degeneration (Wilson disease) is an autosomal recessive monogenic disorder caused by mutations in the ATPase copper transporting beta (ATP7B) gene located on human chromosome 13. This gene encodes a copper-transporting P-type ATPase (ATP7B). Recent studies have revealed that the ATP7B gene is predominantly affected by a few hotspot mutations, with the His1069Gln mutation in exon 14 accounting for 50 to 80% of cases. In China, the Arg778Leu mutation in exon 8 is the most prevalent. However, the discovery of novel mutant genes persists. Case presentation: A 56-year-old Chinese female was referred to our hospital with a liver injury and cirrhosis. Her parents, 2 younger brothers, and children exhibited no signs of liver function impairment. Whole-exome sequencing was conducted on the proband’s genomic DNA, and Sanger sequencing was performed on 6 family members for first-generation verification. Conclusions: We identified a novel c.3715G > T (p.Val1239Phe) variant mutation in the ATP7B gene in the patient. The ATP7B c.3715G > T (p.Val1239Phe) variant is predicted to impact the copper transport P-type ATPase. When combined with another mutant gene to form a compound heterozygous mutation, it can lead to hepatolenticular degeneration. This discovery broadens the range of pathogenic genes in the ATP7B gene.

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Genetic variation spectrum in ATP7B gene identified in Latvian patients with Wilson disease

Cited by 5 publications

References 22 publications

Mutation analysis of the ATP7B gene and genotype–phenotype correlation in Chinese patients with Wilson disease

Mutation analysis of the ATP7B gene and genotype–phenotype correlation in Chinese patients with Wilson disease

Association of variants in the CP, ATOX1 and COMMD1 genes with Wilson disease symptoms in Latvia

A novel mutation in the ATP7B gene causing hepatolenticular degeneration in a Chinese family: A case report

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