A novel homozygous <i><scp>DOCK</scp>8</i> mutation associated with unusual coexistence of gross molluscum contagiosum and epidermodysplasia verruciformis in a <scp>DOCK</scp>8 deficiency patient

Liu, Y.-Q.; Zhang, G.-L.; Mo, Xiaofei; Wang, B.; Wu, Fei; Chen, Jianli; Luo, Hao; Zhu, Lude; Xu, Minyuan; Zhou, Qi; Cai, Qi; Wang, X.-L.

doi:10.1111/jdv.14344

Cited by 13 publications

(8 citation statements)

References 7 publications

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“…Furthermore, T cell function after CD3 stimulation (P3 and P5; Table S2) and B cell function as measured by antibody responses to common DNA and RNA viruses (P1–P5; Table S3) were normal. This finding is also consistent with those for patients with EVER2 deficiency (Crequer et al, 2013) but not for patients with RHOH, MST1, CORO1A, ARTEMIS, RASGRP, DOCK8, and TPP2 deficiencies who suffer from CD4 + T cell lymphopenia and various degrees of impairment of circulating T cell response to CD3 stimulation (Crequer et al, 2012a,b; Sanal et al, 2012; Stray-Pedersen et al, 2014; Stepensky et al, 2015; Tahiat et al, 2016; Liu et al, 2017; Platt et al, 2017). Finally, more detailed analyses of skin-homing T cell populations (CLA + , CCR10 + , CLA + CCR4 + , and CLA + CCR10 + subsets) revealed no frequency abnormalities in the five patients tested (P1–P4 and P15; Table S4), again contrasting with the smaller sizes of these subsets within the CD4 + compartment in RHOH-deficient patients (Table S4; Crequer et al, 2012b).…”

Section: Resultssupporting

confidence: 86%

“…The clinical characteristics of EVER1- and EVER2-deficient patients (EV in the absence of other clinical manifestations; Orth, 2006, 2008; Burger and Itin, 2014) and of the patients with CIB1 deficiency described in this study are identical and markedly different from those of patients with atypical EV due to CD4 + T cell lymphopenia caused by RHOH, MST1 (encoded by STK4 ), CORO1A, ARTEMIS (encoded by DCLRE1C ), DOCK8, RASGRP1, LCK, and TPP2 deficiencies. In such patients, persistent β-HPV–induced lesions occur in the context of a much broader infectious, autoimmune, and tumoral phenotype (Crequer et al, 2012a,b; Sanal et al, 2012; Stray-Pedersen et al, 2014; Stepensky et al, 2015; Li et al, 2016; Tahiat et al, 2016; Liu et al, 2017; Platt et al, 2017). Consistent with this observation, the CIB1-deficient patients tested in this study had no detectable T-lymphocyte defects in terms of either cell numbers or functions.…”

Section: Discussionmentioning

confidence: 99%

“…Patients with an “atypical” form of inherited EV have recently been described (de Jong et al, 2018). These patients suffer from primary immunodeficiencies due to profound T cell defects caused by inactivating biallelic mutations of STK4 (Crequer et al, 2012a), RHOH (Crequer et al, 2012b), CORO1A (Stray-Pedersen et al, 2014), TPP2 (Stepensky et al, 2015), DCLRE1C (Tahiat et al, 2016), LCK (Li et al, 2016), RASGRP1 (Platt et al, 2017), or DOCK8 (Sanal et al, 2012; Liu et al, 2017). Other patients with atypical EV have T cell deficits of unknown genetic etiology (Azzimonti et al, 2005; Borgogna et al, 2014; Landini et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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The human CIB1–EVER1–EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses

Jong

Crequer

Matos

et al. 2018

Journal of Experimental Medicine

101

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Patients with epidermodysplasia verruciformis (EV) and biallelic null mutations of (encoding EVER1) or (EVER2) are selectively prone to disseminated skin lesions due to keratinocyte-tropic human β-papillomaviruses (β-HPVs), which lack E5 and E8. We describe EV patients homozygous for null mutations of the gene encoding calcium- and integrin-binding protein-1 (CIB1). CIB1 is strongly expressed in the skin and cultured keratinocytes of controls but not in those of patients. CIB1 forms a complex with EVER1 and EVER2, and CIB1 proteins are not expressed in EVER1- or EVER2-deficient cells. The known functions of EVER1 and EVER2 in human keratinocytes are not dependent on CIB1, and CIB1 deficiency does not impair keratinocyte adhesion or migration. In keratinocytes, the CIB1 protein interacts with the HPV E5 and E8 proteins encoded by α-HPV16 and γ-HPV4, respectively, suggesting that this protein acts as a restriction factor against HPVs. Collectively, these findings suggest that the disruption of CIB1-EVER1-EVER2-dependent keratinocyte-intrinsic immunity underlies the selective susceptibility to β-HPVs of EV patients.

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Section: Resultssupporting

confidence: 86%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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The human CIB1–EVER1–EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses

Jong

Crequer

Matos

et al. 2018

Journal of Experimental Medicine

101

View full text Add to dashboard Cite

show abstract

“…Inactivating mutations of RHOH ( Crequer et al, 2012b ) , STK4 (encoding the MST1 protein) ( Crequer et al, 2012a ), CORO1A ( Stray-Pedersen et al, 2014 ), DCLRE1C (encoding the Artemis protein) ( Tahiat et al, 2017 ), DOCK8 ( Sanal et al, 2012 ; Liu et al, 2017 ), RASGRP1 ( Platt et al, 2017 ), LCK ( Li et al, 2016 ), and TPP2 ( Stepensky et al, 2015 ) have been reported in patients with atypical EV. Interestingly, the clinical penetrance of these genetic disorders for EV lesions is low, as only a few patients present with manifestations of EV.…”

Section: Human Genetics Of Atypical Evmentioning

confidence: 99%

Epidermodysplasia Verruciformis: Inborn Errors of Immunity to Human Beta-Papillomaviruses

et al. 2018

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Epidermodysplasia verruciformis (EV) is an autosomal recessive skin disorder with a phenotype conditional on human beta-papillomavirus (beta-HPV) infection. Such infections are common and asymptomatic in the general population, but in individuals with EV, they lead to the development of plane wart-like and red or brownish papules or pityriasis versicolor-like skin lesions, from childhood onwards. Most patients develop non-melanoma skin cancer (NMSC), mostly on areas of UV-exposed skin, from the twenties or thirties onwards. At least half of the cases of typical EV are caused by biallelic loss-of-function mutations of TMC6/EVER1 or TMC8/EVER2. The cellular and molecular basis of disease in TMC/EVER-deficient patients is unknown, but a defect of keratinocyte-intrinsic immunity to beta-HPV is suspected. Indeed, these patients are not susceptible to other infectious diseases and have apparently normal leukocyte development. In contrast, patients with an atypical form of EV due to inborn errors of T-cell immunity invariably develop clinical symptoms of EV in the context of other infectious diseases. The features of the typical and atypical forms of EV thus suggest that the control of beta-HPV infections requires both EVER1/EVER2-dependent keratinocyte-intrinsic immunity and T cell-dependent adaptive immunity.

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“…Recently, a limited number of patients with an EV-like phenotype have been described, namely, atypical EV. In contrast to typical EV patients, these patients not only suffer from EV-HPV-associated skin lesions but also co-infections with other viruses, bacteria, and fungi because of the T cell deficits caused by RHOH, IL7, MST1, CORO1A, TPP2, DCLRE1C, LCK, RASGRP1, and DOCK8 deficiencies (Crequer et al, 2012a,b;Stray-Pedersen et al, 2014;Horev et al, 2015;Stepensky et al, 2015;Li et al, 2016;Liu et al, 2017;Platt et al, 2017;Tahiat et al, 2017). More than 500 cases of typical EV have been described across different racial and ethnic groups, and several EV patients have been reported among the Chinese population; however, few of them have undergone detailed genetic analysis.…”

Section: Introductionmentioning

confidence: 99%

Identification and Splicing Characterization of Novel TMC6 and TMC8 Variants Associated With Epidermodysplasia Verruciformis in Three Chinese Families

et al. 2021

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Background: Epidermodysplasia verruciformis (EV) is a rare genodermatosis characterized by abnormal susceptibility to human beta papillomavirus infections and a particular propensity to develop non-melanoma skin cancers (NMSCs). The majority of EV cases are caused by biallelic null variants in TMC6, TMC8, and CIB1. This study aimed to identify disease-causing variants in three Chinese families with EV and to elucidate their molecular pathogenesis.Methods: Genomic DNA from the probands of three EV families was analyzed by whole-exome sequencing (WES). cDNA sequencing was performed to investigate abnormal splicing of the variants. Quantitative RT-PCR (qRT-PCR) was conducted to quantify the mRNA expression of mutant TMC6 and TMC8.Results: Whole-exome sequencing identified two novel homozygous variants (c.2278-2A > G in TMC6 and c.559G > A in TMC8) in families 1 and 2, respectively. In family 3, WES revealed a recurrent and a novel compound heterozygous variant, c.559G > A and c.1389G > A, in TMC8. The c.2278-2A > G TMC6 variant led to the skipping of exon 19 and resulted in premature termination at codon 776. Subsequent qRT-PCR revealed that the aberrantly spliced transcript was partly degraded. Notably, the TMC8 c.559G > A variant created a novel acceptor splice site at c.561 and yielded three different aberrant transcripts. qRT-PCR revealed that most of the mutant transcripts were degraded via nonsense-mediated mRNA decay (NMD).Conclusion: We identified three novel disease-causing variants in TMC6 or TMC8 in three Chinese families with EV. The EV phenotypes of the three patients were due to a reduction in TMC6 or TMC8. Our findings expand the genetic causes of EV in the Chinese population.

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A novel homozygous DOCK8 mutation associated with unusual coexistence of gross molluscum contagiosum and epidermodysplasia verruciformis in a DOCK8 deficiency patient

Cited by 13 publications

References 7 publications

The human CIB1–EVER1–EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses

The human CIB1–EVER1–EVER2 complex governs keratinocyte-intrinsic immunity to β-papillomaviruses

Epidermodysplasia Verruciformis: Inborn Errors of Immunity to Human Beta-Papillomaviruses

Identification and Splicing Characterization of Novel TMC6 and TMC8 Variants Associated With Epidermodysplasia Verruciformis in Three Chinese Families

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