Novel recessive <i>PDZD7</i> biallelic mutations in two Chinese families with non‐syndromic hearing loss

Guan, Jing; Wang, Hongyang; Lan, Lan; Wang, Li; Yang, Ju Dong; Xie, Linyi; Yin, Zifang; Xiong, Wenping; Zhao, Lidong; Wang, Dayong

doi:10.1002/ajmg.a.38477

Cited by 17 publications

(21 citation statements)

References 13 publications

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“…In eight recessive probands, bi-allelic mutations, confirmed by parental genotyping, were identified in known deafness genes OTOF, CDH23, PCDH15, ADGRV1, PDZD7, KARS, OTOG and GRXCR2. (n = 1 each, Table 1 The previous report has associated PDZD7 mutations with digenic Usher syndrome(13) and DFNB57 (14,15). To our knowledge, our study is the third report to identify PDZD7 as a causative gene for autosomal recessive non-syndromic hearing loss (ARNSHL) in the Chinese population (14,15 (19,20).…”

Section: Genetic Findingsmentioning

confidence: 72%

“…(n = 1 each, Table 1 The previous report has associated PDZD7 mutations with digenic Usher syndrome(13) and DFNB57 (14,15). To our knowledge, our study is the third report to identify PDZD7 as a causative gene for autosomal recessive non-syndromic hearing loss (ARNSHL) in the Chinese population (14,15 (19,20). Phenotypic characterization of Family NT-50 shows that the p.R426 X mutation in GRHL2 resulted in progressive, bilateral hearing loss with a typical onset in middle adulthood, which was consistent with the phenotype reported for the other two DFNA28 families (19,20).…”

Section: Genetic Findingsmentioning

confidence: 99%

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Clinical and genetic study of twelve Chinese Han families with non-syndromic deafness

Huang

et al. 2019

Preprint

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BACKGROUND: Non-syndromic hearing loss is clinically and genetically heterogeneous. In this study, we characterized the clinical features of twelve Chinese Han deaf families in which mutations in common deafness genes GJB2 , SLC26A4 and MT-RNR1 were excluded. RESULTS: Targeted next-generation sequencing of 147 known deafness genes was performed in probands of ten families, while whole-exome sequencing was applied in those of the rest two. Pathogenic mutations in a total of 11 rare deafness genes, OTOF , CDH23 , PCDH15 , PDZD7 , ADGRV1 , KARS , OTOG , GRXCR2 , MYO6 , GRHL2 , and POU3F4 , were identified in all 12 probands, with 17 mutations being novel. Intrafamilial co-segregation of the mutations and the deafness phenotype were confirmed by Sanger sequencing. CONCLUSIONS: Our results expanded the mutation spectrum and genotype-phenotype correlation of non-syndromic hearing loss in Chinese Hans and also emphasized the importance of combining both next-generation sequencing and detailed auditory evaluation to achieve a more accurate diagnosis for non-syndromic hearing loss.

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Section: Genetic Findingsmentioning

confidence: 72%

Section: Genetic Findingsmentioning

confidence: 99%

Clinical and genetic study of twelve Chinese Han families with non-syndromic deafness

Huang

et al. 2019

Preprint

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“…The web server versions of these tools were used under their default settings. We performed three-dimensional (3D) protein modelling of mutational and wild-type proteins, and the protein structure was visualized by Swiss-PDB Viewer (Guan et al, 2018).…”

Section: In Silico Analysis and Molecular Structural Modelingmentioning

confidence: 99%

Functional characterization of the chlorzoxazone 6-hydroxylation activity of human cytochrome P450 2E1 allelic variants in Han Chinese

Wang

et al. 2020

PeerJ

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Backgrounds Cytochrome P450 (P450) 2E1 is one of the primary enzymes responsible for the metabolism of xenobiotics, such as drugs and environmental carcinogens. The genetic polymorphisms of the CYP2E1 gene in promoter and coding regions have been identified previously in the Han Chinese population from four different geographic areas of Mainland China. Methods To investigate whether genetic variants identified in the CYP2E1 coding region affect enzyme function, the enzymes of four single nucleotide polymorphism (SNP) variants in the coding region (novel c.1009C>T, causing p.Arg337X, where X represents the translational stop codon; c.227G>A, causing p.Arg76His; c.517G>A, yielding p.Gly173Ser; and c.1263C>T, presenting the highest allele frequency), two novel alleles (c.[227G>A;1263C>T] and c.[517G>A;1263C>T]), and the wild-type CYP2E1 were heterologously expressed in COS-7 cells and functionally characterized in terms of expression level and chlorzoxazone 6-hydroxylation activity. The impact of the CYP2E1 variant sequence on enzyme activity was predicted with three programs: Polyphen 2, PROVEAN and SIFT. Results The prematurely terminated p.Arg337X variant enzyme was undetectable by western blotting and inactive toward chlorzoxazone 6-hydroxylation. The c.1263C>T and c.[517G>A;1263C>T] variant enzymes exhibited properties similar to those of the wild-type CYP2E1. The CYP2E1 variants c.227G>A and c.[227G>A;1263C>T] displayed significantly reduced enzyme activity relative to that of the wild-type enzyme (decreased by 42.8% and 32.8%, respectively; P < 0.01). The chlorzoxazone 6-hydroxylation activity of the c.517G>A transfectant was increased by 31% compared with the wild-type CYP2E1 enzyme (P < 0.01). Positive correlations were observed between the protein content and enzyme activity for CYP2E1 (P = 0.0005, r2 = 0.8833). The characterization of enzyme function allelic variants in vitro was consistent with the potentially deleterious effect of the amino acid changes as determined by prediction tools. Conclusions These findings indicate that the genetic polymorphisms of CYP2E1, i.e., c.1009C>T (p.Arg337X), c.227G>A (p.Arg76His), and c.517G>A (p.Gly173Ser), could influence the metabolism of CYP2E1 substrates, such as chlorzoxazone.

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“…In a PDZD7 -knockdown zebrafish model, an USH-like phenotype, exacerbation of retinal cell death, and reduction in ADGRV1 localization in the connecting cilium were observed [6]. Interestingly, PDZD7 was reported to be a causative gene of DFNB57 [9,10,11,12,13,14]. The morphological and functional roles of PDZD7 in the organization of cochlear hair cells have been validated in vivo and in vitro.…”

Section: Introductionmentioning

confidence: 99%

“…To the best of our knowledge, all reported subjects with biallelic variants of PDZD7 demonstrate autosomal-recessive, non-syndromic hearing loss (ARNSHL) without a visual phenotype, whereas monoallelic variants of PDZD7 act as genetic modifiers of USH2. In other words, the identification of biallelic recessive variants in PDZD7 seems to be a pathognomonic sign of ARNSHL [9,10,11,12,13,14], suggesting that diverse phenotypes could be related to PDZD7 variants and the presence of possible genotype–phenotype correlations. However, ARNSHL in association with biallelic PDZD7 variants has only been reported in 10 families to date in the literature [10,11,12,13,14,15], mostly without longer-term follow-ups for hearing loss and RP.…”

Section: Introductionmentioning

confidence: 99%

Identification of a Potential Founder Effect of a Novel PDZD7 Variant Involved in Moderate-to-Severe Sensorineural Hearing Loss in Koreans

Lee

Han

Kim

et al. 2019

IJMS

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PDZD7, a PDZ domain-containing scaffold protein, is critical for the organization of Usher syndrome type 2 (USH2) interactome. Recently, biallelic PDZD7 variants have been associated with autosomal-recessive, non-syndromic hearing loss (ARNSHL). Indeed, we identified novel, likely pathogenic PDZD7 variants based on the American College of Medical Genetics and Genomics/Association for Molecular Pathology (ACMG/AMP) guidelines from Korean families manifesting putative moderate-to-severe prelingual ARNSHL; these were c.490C>T (p.Arg164Trp), c.1669delC (p.Arg557Glyfs*13), and c.1526G>A (p.Gly509Glu), with p.Arg164Trp being a predominantly recurring variant. Given the recurring missense variant (p.Arg164Trp) from our cohort, we compared the genotyping data using six short tandem-repeat (STR) markers within or flanking PDZD7 between four probands carrying p.Arg164Trp and 81 normal-hearing controls. We observed an identical haplotype across three out of six STR genotyping markers exclusively shared by two unrelated hearing impaired probands but not by any of the 81 normal-hearing controls, suggesting a potential founder effect. However, STR genotyping, based on six STR markers, revealed various p.Arg164Trp-linked haplotypes shared by all of the affected subjects. In conclusion, PDZD7 can be an important causative gene for moderate to severe ARNSHL in Koreans. Moreover, at least some, if not all, p.Arg164Trp alleles in Koreans could exert a potential founder effect and arise from diverse haplotypes as a mutational hot spot.

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Novel recessive PDZD7 biallelic mutations in two Chinese families with non‐syndromic hearing loss

Cited by 17 publications

References 13 publications

Clinical and genetic study of twelve Chinese Han families with non-syndromic deafness

Clinical and genetic study of twelve Chinese Han families with non-syndromic deafness

Functional characterization of the chlorzoxazone 6-hydroxylation activity of human cytochrome P450 2E1 allelic variants in Han Chinese

Identification of a Potential Founder Effect of a Novel PDZD7 Variant Involved in Moderate-to-Severe Sensorineural Hearing Loss in Koreans

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