Whole‐exome sequencing identifies novel pathogenic variants across the <i>ATP7B </i>gene and some modifiers of Wilson's disease phenotype

Kluska, Anna; Kulecka, Maria; Litwin, Tomasz; Dzieżyc, Karolina; Bałabas, Aneta; Piątkowska, Magdalena; Paziewska, Agnieszka; Dąbrowska, Michalina; Mikula, Michał; Kamińska, Diana; Wiernicka, Anna; Socha, Piotr; Członkowska, Anna; Ostrowski, Jerzy

doi:10.1111/liv.13967

Cited by 40 publications

(27 citation statements)

References 53 publications

(90 reference statements)

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“…We suspect that two mutations confirmed as pathogenic, in our case, were present on one allele (uniparental isodisomy), which is rare but has been previously observed [9]. In our recent study of 248 patients with WD, we found three cases with three mutations [10]. As WD is an autosomal recessive disease, pathogenic mutations must be present on two alleles [2].…”

Section: To the Editorssupporting

confidence: 68%

Pitfalls in diagnosing Wilson’s Disease by genetic testing alone: the case of a 47-year-old woman with two pathogenic variants of the ATP7B gene

Antos

Litwin

Skowrońska

et al. 2020

Neurol Neurochir Pol.

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Section: To the Editorssupporting

confidence: 68%

Pitfalls in diagnosing Wilson’s Disease by genetic testing alone: the case of a 47-year-old woman with two pathogenic variants of the ATP7B gene

Antos

Litwin

Skowrońska

et al. 2020

Neurol Neurochir Pol.

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“…Another reason may be due to the presence of mutations outside the open reading frame of the gene, i.e., in the promoter, introns, the presence of gene rearrangements or possible mutations in other copper-transport chaperone gene. Anna Kluska proved that rare allelic variants in ESD and IN080 increased and decreased the chances for the neurologic phenotype, respectively, while rare variants in APOE and MBD6 decreased the possibilities of WD early manifestation [ 28 ]. It was reported that the AmpliSeq Exome kit usually underestimated the insertions and deletions in exome enrichment products [ 28 ].…”

Section: Discussionmentioning

confidence: 99%

“…Anna Kluska proved that rare allelic variants in ESD and IN080 increased and decreased the chances for the neurologic phenotype, respectively, while rare variants in APOE and MBD6 decreased the possibilities of WD early manifestation [ 28 ]. It was reported that the AmpliSeq Exome kit usually underestimated the insertions and deletions in exome enrichment products [ 28 ].…”

Section: Discussionmentioning

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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“…Over hundred mutations of ATP7B, including point mutations, deletions and frame-shift, have been reported in patients with WD. Most patients have two different mutations of the gene on each allele encoding the WD gene, called compound heterozygotes [2,3]. This protein product is similar to other ATP-dependent transporters for heavy metals, which is mainly expressed in the liver and mediates copper homeostasis in liver cells.…”

Section: Introductionmentioning

confidence: 99%

Characterization of Fibrinogen as a Key Modulator in Patients with Wilson’s Diseases with Functional Proteomic Tools

Wang

Lin

Hung

et al. 2019

IJMS

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Wilson’s disease (WD) is an autosomal recessive disorder of copper metabolism caused by defects in the ATPase gene (ATP7B). The various clinical features result from the massive accumulation of copper in the liver, cornea and basal ganglia. Although WD can be effectively treated with proper medicine, this disease is difficult to clearly diagnose due to its indefinite symptoms. In the current study, we achieved a positive correlation between clinical symptoms and the enzymatic activity of ceruloplasmin in WD patients. Furthermore, proteome profiles of plasma as well as network analysis demonstrated that fibrinogen is a critical indicator which is significantly unregulated in WD subjects in comparison to healthy donors and closely linked to pathogenesis of WD. Here, we applied 2DE-immunoblots and immunohistochemistry to verify the protein level and localization in situ. The enhanced expression of fibrinogen in the plasma of WD subjects with respect to that of healthy controls and patients with distinct disorders was also confirmed by utilizing clinical samples. As expected, application of high dose of copper induced expression of fibrinogen, while knockdown of ceruloplasmin also resulted in upregulation of fibrinogen as well as elimination of superoxide dismutase (SOD), leading to increased oxidative stress in cells. In summary, the liver injury or oxidative stress induced by the progression of WD may account for the obvious increase of fibrinogen, which in turn triggers inflammatory responses and interferes coagulation cascades; this finding sheds light on the early detection and diagnosis of WD.

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Whole‐exome sequencing identifies novel pathogenic variants across the ATP7B gene and some modifiers of Wilson's disease phenotype

Abstract: In a Polish population, genetic screening for WD may help genotype for four variants (p.His1069Gln, p.Gln1351Ter, p.Trp779Ter and c.3402delC), with direct sequencing of all ATP7B amplicons as a second diagnostic step. We also identified some allelic variants that may modify a WD phenotype.

Cited by 40 publications

References 53 publications

Pitfalls in diagnosing Wilson’s Disease by genetic testing alone: the case of a 47-year-old woman with two pathogenic variants of the ATP7B gene

Pitfalls in diagnosing Wilson’s Disease by genetic testing alone: the case of a 47-year-old woman with two pathogenic variants of the ATP7B gene

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

Characterization of Fibrinogen as a Key Modulator in Patients with Wilson’s Diseases with Functional Proteomic Tools

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