Confirmation of PDZD7 as a Nonsyndromic Hearing Loss Gene

Vona, Barbara; Lechno, Stanislav; Hofrichter, Michaela A.H.; Hopf, Susanne; Läig, Anne K; Haaf, Thomas; Keilmann, Annerose; Zechner, Ulrich; Bartsch, Oliver

doi:10.1097/aud.0000000000000278

Cited by 28 publications

(29 citation statements)

References 30 publications

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“…Originally identified as a modifier gene for Usher syndrome type 2 genes, PDZD7 has more recently been identified as a nonsyndromic deafness gene itself (Booth et al, 2015; Vona et al, 2016). Genetics experiments showed that positioning of ADGRV1 at ankle links depends critically on PDZD7 (Zou et al, 2014); consistent with those results, PDZD7 binds directly to ADGRV1 (Chen et al, 2014).…”

Section: Discussionmentioning

confidence: 99%

PDZD7-MYO7A complex identified in enriched stereocilia membranes

Morgan

Krey

Grati

et al. 2016

eLife

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While more than 70 genes have been linked to deafness, most of which are expressed in mechanosensory hair cells of the inner ear, a challenge has been to link these genes into molecular pathways. One example is Myo7a (myosin VIIA), in which deafness mutations affect the development and function of the mechanically sensitive stereocilia of hair cells. We describe here a procedure for the isolation of low-abundance protein complexes from stereocilia membrane fractions. Using this procedure, combined with identification and quantitation of proteins with mass spectrometry, we demonstrate that MYO7A forms a complex with PDZD7, a paralog of USH1C and DFNB31. MYO7A and PDZD7 interact in tissue-culture cells, and co-localize to the ankle-link region of stereocilia in wild-type but not Myo7a mutant mice. Our data thus describe a new paradigm for the interrogation of low-abundance protein complexes in hair cell stereocilia and establish an unanticipated link between MYO7A and PDZD7.DOI: http://dx.doi.org/10.7554/eLife.18312.001

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Section: Discussionmentioning

confidence: 99%

PDZD7-MYO7A complex identified in enriched stereocilia membranes

Morgan

Krey

Grati

et al. 2016

eLife

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“…PDZD7 encodes a PDZ domain‐containing scaffold protein; the largest transcript (NM_001195263.1) of PDZD7 encodes 17 exons, and it has been implicated as an ARNSHL‐associated gene (Booth et al, 2015; Le Quesne Stabej et al, 2017; Schneider et al, 2009; Vona et al, 2016) and a modifier and candidate gene for human USH2 (Ebermann et al, 2010). In this study, next generation sequencing (NGS) was used to find the disease‐causing gene of two Chinese families with ARNSHL (Figure 1a and 1b), and we identified two biallelic mutations in the PDZD7 gene.…”

Section: Discussionmentioning

confidence: 99%

“…A homozygous disruption of PDZD7 by reciprocal translocation was found in a 9‐year‐old boy with non‐syndromic congenital sensorineural hearing loss (Schneider et al, 2009). Clinical tracking of this patient over 6 years showed that the proband demonstrated stable sensorineural hearing loss and healthy retinas at the age of 15.5 years (Vona et al, 2016). To date, only seven biallelic mutations of the monogenic PDZD7 have been validated—in two German families, four Iranian families, and a Pakistani family with ARNSHL (Booth et al, 2015; Le Quesne Stabej et al, 2017; Vona et al, 2016).…”

Section: Introductionmentioning

confidence: 99%

“…Clinical tracking of this patient over 6 years showed that the proband demonstrated stable sensorineural hearing loss and healthy retinas at the age of 15.5 years (Vona et al, 2016). To date, only seven biallelic mutations of the monogenic PDZD7 have been validated—in two German families, four Iranian families, and a Pakistani family with ARNSHL (Booth et al, 2015; Le Quesne Stabej et al, 2017; Vona et al, 2016). Outside of the Iranian, German and Pakistani populations, little is known about the effect of PDZD7 on ARNSHL.…”

Section: Introductionmentioning

confidence: 99%

“…Variations in many genes can cause either non‐syndromic hearing loss or syndromic hearing loss. PDZD7 encodes a PDZ domain‐containing scaffold protein, that was recently implicated as a modifier and candidate gene in human USH2 (Ebermann et al, 2010), and it is an autosomal recessive genetic hearing loss (ARNSHL)‐associated gene (Booth et al, 2015; Le Quesne Stabej et al, 2017; Schneider et al, 2009; Vona et al, 2016). The PDZD7 gene was first identified as being responsible for ARNSHL in a consanguineous German family in 2009.…”

Section: Introductionmentioning

confidence: 99%

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

Guan

Wang

Lan

et al. 2017

American J of Med Genetics Pt A

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Autosomal recessive non‐syndromic hearing loss (ARNSHL) is a highly heterogeneous genetic condition. PDZD7 has emerged as a new genetic etiology of ARNSHL. Biallelic mutations in the PDZD7 gene have been reported in two German families, four Iranian families, and a Pakistani family with ARNSHL. The effect of PDZD7 on ARNSHL in other population has yet to be elucidated. Two Chinese ARNSHL families, each of which had two affected siblings, were included in this study. The families underwent target region capture and high‐throughput sequencing to analyze the exonic, splice‐site, and intronic sequences of 128 genes. Furthermore, 1751 normal Chinese individuals served as controls, and 122 Chinese families segregating with apparent ARNSHL, who had been previously excluded for variants in the common deafness genes GJB2 and SLC26A4, were subjected to screening for candidate mutations. We identified a novel homozygous missense mutation (p.Arg66Leu) and novel compound heterozygous frameshift mutations (p.Arg56fsTer24 and p.His403fsTer36) in Chinese families with ARNSHL. This is the first report to identify PDZD7 as an ARNSHL‐associated gene in the Chinese population. Our finding could expand the pathogenic spectrum and strengthens the clinical diagnostic role of the PDZD7 gene in ARNSHL patients.

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Assessment of Disease‐Associated Sequence Variants and Considerations for Functional Validation using Mouse Models

Cox

2016

Encyclopedia of Life Sciences

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Whole‐exome and whole‐genome sequencing approaches are rapidly becoming mainstream tools accessible to both basic researchers and clinical teams. Likewise, technological advances in genome editing, such as the CRISPR/Cas system, are poised to revolutionise model system research, making it more feasible to create animal models that truly recapitulate the human condition. However, procedures for identifying disease‐associated sequence variants are still far from robust and there are many biological variables that need to be considered when attempting to functionally validate disease‐associated variants. In this article, we highlight the many limitations and issues that should be considered at different stages throughout this process – from the filtering of sequencing data to the selection of variants, and from the selection of the model organism to the appropriate means of phenotyping. Key Concepts Researchers must appreciate the limitations of exome sequencing when considering candidate gene variants. Researchers using sequencing services should ensure they receive the original BAM files of their sequencing data. Common bioinformatic algorithms used to process sequencing data are predictive tools only. Bioinformatic tools should not be used in isolation or their outputs taken as proof of disease causation of a variant. Gene expression in a tissue consistent with that affected in patients can be used to help prioritise candidate genes but is not evidence for causation. Demonstration of a functional impact of a given variant in an in vitro assay is useful but does not necessarily mean it is responsible for the disease of interest. Genetic background of the mouse strain(s) can significantly influence the phenotypic presentation. Researchers using animal models should consider the composition of animal chow when modelling a disease with considerable phenotypic variability.

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Confirmation of PDZD7 as a Nonsyndromic Hearing Loss Gene

Cited by 28 publications

References 30 publications

PDZD7-MYO7A complex identified in enriched stereocilia membranes

PDZD7-MYO7A complex identified in enriched stereocilia membranes

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

Assessment of Disease‐Associated Sequence Variants and Considerations for Functional Validation using Mouse Models

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