CDH23 — cadherin related 23

The CDH23 gene provides instructions for making a protein called cadherin-23. This protein acts like a molecular glue, helping cells stick together and maintain their proper structure. In the human body, cadherin-23 is especially important in two key areas: the inner ear and the retina (the light-sensitive tissue at the back of the eye). In the inner ear, it helps form tiny hair-like structures that are essential for hearing and balance. In the eye, it supports the cells responsible for detecting light, allowing us to see. When there are harmful changes (mutations) in the CDH23 gene, the cadherin-23 protein may be produced incorrectly or not at all. This disrupts the normal function of the inner ear and the retina. Depending on the specific mutation, this can lead to two main conditions. The more severe condition is Usher syndrome type 1D, which causes profound hearing loss from birth, severe balance issues, and a progressive loss of vision known as retinitis pigmentosa. A milder condition caused by different mutations in the same gene is called DFNB12, which causes hearing loss but typically does not affect vision or balance. These conditions are inherited in an autosomal recessive pattern. This means that for a person to have the disease, they must inherit two mutated copies of the CDH23 gene—one from each parent. The parents, who each carry one mutated copy and one normal copy, are called carriers. Carriers typically do not show any symptoms of the condition. If both parents are carriers, there is a 25% chance with each pregnancy that their child will inherit both mutated copies and develop the disorder. Understanding this inheritance pattern is important for families when considering genetic testing and family planning.

Gene description: CDH23 encodes a protocadherin involved in the development and maintenance of mechanotransduction in the inner ear and retina.

Patient and family guide: The CDH23 gene provides instructions for making a protein called cadherin-23. This protein acts like a molecular glue, helping cells stick together and maintain their proper structure. In the human body, cadherin-23 is especially important in two key areas: the inner ear and the retina (the light-sensitive tissue at the back of the eye). In the inner ear, it helps form tiny hair-like structures that are essential for hearing and balance. In the eye, it supports the cells responsible for detecting light, allowing us to see. When there are harmful changes (mutations) in the CDH23 gene, the cadherin-23 protein may be produced incorrectly or not at all. This disrupts the normal function of the inner ear and the retina. Depending on the specific mutation, this can lead to two main conditions. The more severe condition is Usher syndrome type 1D, which causes profound hearing loss from birth, severe balance issues, and a progressive loss of vision known as retinitis pigmentosa. A milder condition caused by different mutations in the same gene is called DFNB12, which causes hearing loss but typically does not affect vision or balance. These conditions are inherited in an autosomal recessive pattern. This means that for a person to have the disease, they must inherit two mutated copies of the CDH23 gene—one from each parent. The parents, who each carry one mutated copy and one normal copy, are called carriers. Carriers typically do not show any symptoms of the condition. If both parents are carriers, there is a 25% chance with each pregnancy that their child will inherit both mutated copies and develop the disorder. Understanding this inheritance pattern is important for families when considering genetic testing and family planning.

Gene function: CDH23 plays a crucial role in retinal photoreceptor development and function, particularly in maintaining the structural integrity of the photoreceptor outer segments. It is involved in cell adhesion and signal transduction pathways essential for light perception. Mutations disrupt these processes, leading to photoreceptor degeneration and vision loss, characteristic of certain inherited retinal diseases.

Protein structure: The CDH23 gene encodes cadherin-23, a large single-pass type I transmembrane protein. The full-length human protein consists of 3,354 amino acids. Its structure is characterized by a massive extracellular domain, a single transmembrane segment, and a relatively short intracellular domain. The extracellular portion is composed of 27 tandemly repeated cadherin (EC) domains. These EC domains contain highly conserved calcium-binding motifs; the binding of calcium ions is crucial for rigidifying the extracellular structure, allowing it to extend outward from the cell surface and participate in adhesion. Unlike classical cadherins, the N-terminus of cadherin-23 contains specific polar amino acids that are essential for its interaction with other proteins. In the inner ear, cadherin-23 assembles into functional complexes by forming homodimers (binding to another cadherin-23 molecule) or heterodimers, most notably interacting with protocadherin-15 (PCDH15) to form the tip links of hair cell stereocilia. The protein undergoes alternative splicing, generating various isoforms that differ primarily in their cytoplasmic domains, which may dictate tissue-specific interactions with intracellular scaffolding proteins.

Molecular function: The CDH23 gene encodes cadherin-23, a calcium-dependent cell-cell adhesion glycoprotein belonging to the cadherin superfamily. At the molecular level, cadherin-23 functions primarily by mediating homophilic and heterophilic interactions between adjacent cells or cellular structures. In the inner ear, cadherin-23 is a critical structural component of the tip links, which are fine extracellular filaments connecting the stereocilia of sensory hair cells. These tip links are essential for the mechanotransduction process, where the mechanical force of sound waves or head movements is converted into electrical signals. Cadherin-23 interacts with another Usher syndrome protein, protocadherin-15 (PCDH15), to form these functional tip link complexes. In the retina, the molecular function of cadherin-23 is less completely understood but is believed to be crucial for the structural integrity and function of photoreceptor cells. It is thought to participate in the organization and maintenance of the photoreceptor outer segments, possibly by mediating adhesion between the outer segment discs or between the photoreceptors and the adjacent retinal pigment epithelium (RPE). The calcium-binding properties of its extracellular cadherin repeats are vital for maintaining the rigid, extended conformation necessary for its adhesive functions in both the inner ear and the retina.

Expression pattern: The CDH23 gene exhibits a highly specific tissue expression pattern, primarily localized to the inner ear and the retina. In the inner ear, CDH23 is expressed in the sensory hair cells of both the cochlea and the vestibular system. It is a crucial component of the tip links, lateral links, and kinocilial links that connect the stereocilia of these hair cells. The expression is developmentally regulated, playing a vital role in the initial formation and organization of the hair bundles during embryogenesis and early postnatal development. In the eye, CDH23 is strongly expressed in the retina, specifically within the photoreceptor cells. While its exact localization and function in the human retina are still being fully characterized, it is believed to be involved in the structural maintenance and function of the photoreceptor outer segments. Different isoforms of the CDH23 protein are expressed in these tissues; for instance, a shorter isoform is predominantly found in the retina, while longer isoforms are expressed in the inner ear, reflecting tissue-specific functional requirements.

Mutation spectrum: The mutation spectrum of the CDH23 gene is broad and highly heterogeneous, with hundreds of pathogenic variants identified to date. These include missense, nonsense, frameshift, and splice-site mutations, as well as large genomic deletions and duplications. The mutations are distributed throughout the entire length of the gene, affecting various cadherin repeats and the intracellular domain. While there are no universally predominant hotspot regions, certain mutations are more prevalent in specific populations due to founder effects. For example, specific missense mutations are recognized as significant causes of non-syndromic hearing loss in East Asian populations. The type of mutation strongly correlates with the resulting phenotype; truncating mutations generally lead to the more severe Usher syndrome type 1D, whereas missense mutations are often associated with the milder non-syndromic hearing loss (DFNB12).

Pathogenic variants: 1. p.Arg1746Gln (c.5237G>A) - A well-characterized missense variant often associated with a specific phenotype of retinitis pigmentosa that spares the superior retina in Usher syndrome type 1D. 2. p.Pro240Leu (c.719C>T) - A missense mutation frequently reported in cases of non-syndromic hearing loss (DFNB12), demonstrating the genotype-phenotype correlation where missense changes often lead to milder disease. 3. p.Arg2029* (c.6085C>T) - A nonsense mutation resulting in premature protein truncation, typically causing the severe Usher syndrome type 1D phenotype due to loss of protein function. 4. c.113-2A>G - An essential splice-site mutation that disrupts normal mRNA splicing, leading to a non-functional protein and resulting in Usher syndrome type 1D. 5. p.Gln1716* (c.5146C>T) - Another truncating nonsense mutation commonly found in patients with Usher syndrome type 1D, contributing to the profound deafness and progressive vision loss characteristic of the disorder.

Clinical significance: Mutations in the CDH23 gene manifest clinically in two primary ways: Usher syndrome type 1D (USH1D) and non-syndromic hearing loss (DFNB12). USH1D is an autosomal recessive condition characterized by profound congenital sensorineural hearing loss, vestibular areflexia (balance issues), and progressive vision loss due to retinitis pigmentosa (RP). The hearing loss is typically prelingual and severe to profound, often requiring cochlear implantation early in life. Vestibular dysfunction is present from birth, leading to delayed motor milestones such as walking. The visual symptoms in USH1D, caused by retinitis pigmentosa, usually begin in childhood or early adolescence. Patients first experience nyctalopia (night blindness), followed by a progressive constriction of the peripheral visual field, eventually leading to "tunnel vision." Over time, central vision and color vision may also be affected, though macular function is often relatively spared until later stages of the disease. Despite the early onset of symptoms, the progression of retinal degeneration in USH1D is generally slow, with a wide window of macular preservation. In contrast, DFNB12 is characterized by non-syndromic, autosomal recessive hearing loss without the accompanying visual or vestibular deficits seen in Usher syndrome. The hearing loss in DFNB12 is also prelingual and can range from severe to profound. Interestingly, some individuals initially diagnosed with DFNB12 may later develop mild or atypical retinitis pigmentosa, blurring the lines between the two clinical entities and highlighting the phenotypic variability associated with CDH23 mutations.

Inheritance: Autosomal Recessive

Chromosomal location: 10q21.1

Genotype-phenotype correlations: There is a well-established genotype-phenotype correlation for mutations in the CDH23 gene. The severity of the clinical manifestation largely depends on the type and location of the mutation and its impact on protein function. Null mutations, such as nonsense, frameshift, and essential splice-site variants, typically result in a complete loss of functional CDH23 protein. These severe mutations are primarily associated with Usher syndrome type 1D (USH1D), characterized by profound deafness, vestibular dysfunction, and retinitis pigmentosa. Conversely, missense mutations, which often result in a partially functional protein, are more commonly associated with non-syndromic hearing loss (DFNB12). In these cases, the residual protein function is sufficient to maintain retinal and vestibular function but inadequate for normal hearing. However, this correlation is not absolute. Some missense mutations can cause atypical or milder forms of Usher syndrome, and certain combinations of alleles in compound heterozygotes can lead to intermediate phenotypes. The specific location of the missense mutation within the cadherin domains may also influence the clinical outcome.

Research and therapeutic approaches: Currently, there are no FDA-approved disease-modifying therapies or cures for CDH23-related Usher syndrome or non-syndromic hearing loss. Management is primarily supportive and focuses on early intervention to maximize communication and mobility. For hearing loss, this typically involves the use of hearing aids or, more commonly for severe-to-profound cases, bilateral cochlear implantation, which is most effective when performed early in life. Vestibular dysfunction is managed through physical therapy and occupational therapy to help children develop compensatory balance strategies. For the visual impairment (retinitis pigmentosa), management includes routine ophthalmologic monitoring, the use of low-vision aids, and UV protection. Research into targeted therapeutic approaches is ongoing, though the large size of the CDH23 gene (coding sequence >10 kb) presents a significant challenge for traditional adeno-associated virus (AAV) gene therapy, as it exceeds the packaging capacity of standard AAV vectors. To overcome this, researchers are exploring dual-AAV vector systems, where the gene is split into two halves that recombine within the target cell, or the use of alternative delivery vehicles with larger capacities, such as lentiviruses or non-viral nanoparticles. Other investigational strategies include antisense oligonucleotides (ASOs) and splice-switching oligonucleotides, which aim to correct specific splicing defects caused by certain CDH23 mutations. For example, research in animal models has explored targeting specific exons to restore functional protein expression. Additionally, gene editing technologies like CRISPR/Cas9 are being investigated in preclinical models as a potential method to permanently correct specific pathogenic variants at the genomic level.

Diagnostic testing: Diagnostic testing for CDH23-related disorders typically involves molecular genetic testing to identify pathogenic variants in the gene. This is often achieved through next-generation sequencing (NGS) approaches, such as targeted gene panels for retinal dystrophies or hearing loss, whole-exome sequencing (WES), or whole-genome sequencing (WGS). These comprehensive methods are preferred due to the large size of the CDH23 gene and the genetic heterogeneity of Usher syndrome and non-syndromic hearing loss. Genetic counseling is a critical component of the diagnostic process. Since CDH23-related conditions follow an autosomal recessive inheritance pattern, parents of an affected individual are obligate carriers and have a 25% chance of having another affected child in each pregnancy. Carrier testing for at-risk family members and prenatal or preimplantation genetic diagnosis can be offered if the pathogenic variants in the family are known. Early diagnosis is crucial for timely interventions, such as cochlear implantation for hearing loss and specialized educational support for dual sensory impairment.

Animal models: Animal models have been instrumental in understanding the function of CDH23 and the pathogenesis of associated diseases. The most prominent model is the waltzer (v) mouse, which carries mutations in the Cdh23 gene. These mice exhibit profound deafness and vestibular dysfunction, characterized by circling behavior and head tossing, mirroring the inner ear phenotype of human Usher syndrome type 1D. Studies on waltzer mice revealed that CDH23 is essential for the proper organization of stereocilia bundles in hair cells, as its absence leads to splayed and disorganized bundles. Zebrafish models have also provided valuable insights, particularly regarding the role of cdh23 in the retina. While the exact function of CDH23 in primate photoreceptors is still being elucidated, zebrafish studies have shown that cdh23 affects rod cell phototransduction. However, it is noted that the expression pattern and specific functions of CDH23 may differ between zebrafish and mammals, as some studies indicate distinct roles in the human and zebrafish retinas. These models continue to be crucial for testing potential therapeutic interventions, including gene therapy and splice-switching oligonucleotides.

Population genetics: The carrier frequency and prevalence of CDH23 mutations vary significantly among different populations. While Usher syndrome type 1 is generally rare, CDH23 mutations are a major cause of the disorder globally. In certain populations, specific founder mutations have been identified, leading to a higher prevalence of the disease in those groups. For instance, specific CDH23 variants are recognized as one of the most important causes of non-syndromic hearing loss in East Asian populations. Overall, the carrier frequency for CDH23-related disorders in the general population is estimated to be relatively low, but it can be higher in communities with high rates of consanguinity or specific founder effects.

Selected references: 1. Bolz H, et al. Mutation of CDH23, encoding a new member of the cadherin gene family, causes Usher syndrome type 1D. Nat Genet, 2001. PMID: 11138009 2. Bork JM, et al. Usher syndrome 1D and nonsyndromic autosomal recessive deafness DFNB12 are caused by allelic mutations of the novel cadherin-like gene CDH23. Am J Hum Genet, 2001. PMID: 11133364 3. Astuto LM, et al. CDH23 mutation and phenotype heterogeneity: a profile of 107 diverse families with Usher syndrome and nonsyndromic deafness. Am J Hum Genet, 2002. PMID: 12075507 4. Siemens J, et al. Cadherin 23 is a component of the tip link in hair-cell stereocilia. Nature, 2004. PMID: 15057245 5. de Guimaraes TAC, et al. CDH23-Associated Usher Syndrome: Clinical Features and Natural History. Invest Ophthalmol Vis Sci, 2024. PMID: 38451532 6. Oshima A, et al. Mutation profile of the CDH23 gene in 56 probands with Usher syndrome type I. Hum Mutat, 2008. PMID: 18383330 7. Schultz JM, et al. Allelic hierarchy of CDH23 mutations causing non-syndromic deafness DFNB12 or Usher syndrome USH1D in compound heterozygotes. J Med Genet, 2011. PMID: 21940737