Homozygous disruption of PDZD7 by reciprocal translocation in a consanguineous family: a new member of the Usher syndrome protein interactome causing congenital hearing impairment

Abstract

A homozygous reciprocal translocation, 46,XY,t(10;11),t(10;11), was detected in a boy with non-syndromic congenital sensorineural hearing impairment. Both parents and their four other children were heterozygous translocation carriers, 46,XX,t(10;11) and 46,XY,t(10;11), respectively. Fluorescence in situ hybridization of region-specific clones to patient chromosomes was used to localize the breakpoints within bacterial artificial chromosome (BAC) RP11-108L7 on chromosome 10q24.3 and within BAC CTD-2527F12 on chromosome 11q23.3. Junction fragments were cloned by vector ligation and sequenced. The chromosome 10 breakpoint was identified within the PDZ domain containing 7 (PDZD7) gene, disrupting the open reading frame of transcript PDZD7-C (without PDZ domain) and the 5'-untranslated region of transcript PDZD7-D (with one PDZ and two prolin-rich domains). The chromosome 11 breakpoint was localized in an intergenic segment. Reverse transcriptase-polymerase chain reaction analysis revealed PDZD7 expression in the human inner ear. A murine Pdzd7 transcript that is most similar in structure to human PDZD7-D is known to be expressed in the adult inner ear and retina. PDZD7 shares sequence homology with the PDZ domain-containing genes, USH1C (harmonin) and DFNB31 (whirlin). Allelic mutations in harmonin and whirlin can cause both Usher syndrome (USH1C and USH2D, respectively) and congenital hearing impairment (DFNB18 and DFNB31, respectively). Protein-protein interaction assays revealed the integration of PDZD7 in the protein network related to the human Usher syndrome. Collectively, our data provide strong evidence that PDZD7 is a new autosomal-recessive deafness-causing gene and also a prime candidate gene for Usher syndrome.

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

“…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.…”

“…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.…”

“…The PDZD7 gene was first identified as being responsible for ARNSHL in a consanguineous German family in 2009. 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).…”

Homozygosity for constitutional chromosomal rearrangements: a systematic review with reference to origin, ascertainment and phenotype

“…28 Reciprocal translocations Six reports of homozygosity for a reciprocal translocation were identified, involving five different translocations; t(Y;22); t(3;16); t(17;20); t(7;12) and t(10;11) ( Table 2; cases 11-16). 20,[31][32][33][34] In each instance, a consanguinous parental relationship existed, with each parent being heterozygous for the translocation. Furthermore, with the exception two siblings (cases [13][14], no cases involved the same translocation.…”

“…32,33 In cases 13 and 14, homozygosity for t(7;12) was discovered after evaluation and diagnosis of a rare neurodevelopmental disorder, lissencephaly with cerebellar hypoplasia. 32 The parents were phenotypically normal heterozygote first cousins, with a history of previous episodes of miscarriage.…”