USH1C — Usher syndrome type 1C

The USH1C gene provides instructions for making a protein called harmonin. Harmonin acts like a scaffold or an anchor inside certain cells, helping to organize and hold other important proteins together in a network. This protein network is especially crucial in two parts of the body: the inner ear, where it helps with hearing and balance, and the retina (the light-sensitive tissue at the back of the eye), where it helps maintain the health and function of the cells that detect light. When there is a mutation (a harmful change) in the USH1C gene, the harmonin protein may be formed incorrectly or not at all. Without properly functioning harmonin, the protein networks in the inner ear and retina cannot form or work correctly. This leads to a condition called Usher syndrome type 1C. Children born with this condition are typically profoundly deaf from birth and have severe balance issues, which can delay when they learn to sit or walk. In addition to hearing and balance problems, individuals with USH1C mutations also develop a vision disorder called retinitis pigmentosa. This usually begins in childhood or early adolescence with night blindness and a gradual loss of peripheral (side) vision, creating a "tunnel vision" effect. Over time, the vision loss progresses and can lead to legal blindness. Usher syndrome is inherited in an autosomal recessive pattern, meaning a person must inherit two mutated copies of the gene (one from each parent) to develop the condition. Parents who carry only one mutated copy are typically unaffected but have a 25% chance of passing the condition to their children.

Gene description: Encodes harmonin, a scaffold protein crucial for the development and maintenance of inner ear and retinal photoreceptor cells.

Patient and family guide: The USH1C gene provides instructions for making a protein called harmonin. Harmonin acts like a scaffold or an anchor inside certain cells, helping to organize and hold other important proteins together in a network. This protein network is especially crucial in two parts of the body: the inner ear, where it helps with hearing and balance, and the retina (the light-sensitive tissue at the back of the eye), where it helps maintain the health and function of the cells that detect light. When there is a mutation (a harmful change) in the USH1C gene, the harmonin protein may be formed incorrectly or not at all. Without properly functioning harmonin, the protein networks in the inner ear and retina cannot form or work correctly. This leads to a condition called Usher syndrome type 1C. Children born with this condition are typically profoundly deaf from birth and have severe balance issues, which can delay when they learn to sit or walk. In addition to hearing and balance problems, individuals with USH1C mutations also develop a vision disorder called retinitis pigmentosa. This usually begins in childhood or early adolescence with night blindness and a gradual loss of peripheral (side) vision, creating a "tunnel vision" effect. Over time, the vision loss progresses and can lead to legal blindness. Usher syndrome is inherited in an autosomal recessive pattern, meaning a person must inherit two mutated copies of the gene (one from each parent) to develop the condition. Parents who carry only one mutated copy are typically unaffected but have a 25% chance of passing the condition to their children.

Gene function: In the retina, USH1C plays a role in the organization and stability of the photoreceptor cilium and synapse. It is involved in the transport and localization of other Usher syndrome proteins, essential for proper phototransduction and retinal function. Mutations lead to progressive vision loss.

Protein structure: The USH1C gene encodes a protein called harmonin, which is a multi-domain scaffolding protein. Harmonin is characterized by the presence of three PDZ (PSD-95, DLG, ZO-1) domains, two coiled-coil (CC) domains, and a PST (proline-serine-threonine rich) domain. The PDZ domains are critical for protein-protein interactions, allowing harmonin to bind to specific motifs on other proteins, thereby assembling complex protein networks. The coiled-coil domains are involved in protein oligomerization, enabling harmonin molecules to interact with each other and form larger structural assemblies. Harmonin exists in multiple isoforms due to extensive alternative splicing of the USH1C gene. These isoforms are generally categorized into three main classes (a, b, and c) based on their domain composition and size. Class a isoforms are the shortest and contain the three PDZ domains and one CC domain. Class b isoforms are the longest, containing all domains including the PST domain and a second CC domain, and are predominantly expressed in the inner ear. Class c isoforms are intermediate in size. The different isoforms allow harmonin to perform specialized scaffolding functions in different tissues and cellular compartments.

Molecular function: The USH1C gene encodes harmonin, a scaffold protein that plays a central role in the organization and stabilization of protein networks in sensory cells. Harmonin contains multiple PDZ domains, which are protein-protein interaction modules that allow it to bind to a variety of other proteins, including other Usher syndrome-associated proteins (such as MYO7A, CDH23, and PCDH15). This interaction network, often referred to as the Usher protein interactome, is crucial for the structural integrity and function of sensory cells. In the inner ear, the harmonin-mediated protein complex is essential for the proper development, cohesion, and function of the stereocilia bundles on hair cells, which are responsible for mechanotransduction (the conversion of mechanical sound waves into electrical signals). In the retina, harmonin is involved in the organization of the photoreceptor synapse and the transport of proteins between the inner and outer segments of photoreceptors. It acts as an anchoring protein, ensuring that key functional proteins are correctly localized and stabilized within the cell, thereby maintaining the health and function of the photoreceptors.

Expression pattern: The USH1C gene is primarily expressed in the sensory organs, specifically the inner ear and the retina. In the inner ear, harmonin is highly expressed in the stereocilia of cochlear and vestibular hair cells, where it is essential for the development and maintenance of the mechanotransduction apparatus. Its expression in the ear is critical during early development and remains high throughout life. In the retina, USH1C is expressed in photoreceptor cells (both rods and cones) and in Müller glial cells. Within photoreceptors, harmonin is localized to the synaptic terminals and the inner and outer segments, where it is thought to play a role in the organization of the photoreceptor synapse and the transport of proteins. The gene undergoes extensive alternative splicing, resulting in multiple isoforms that exhibit tissue-specific expression patterns, with certain isoforms being more predominant in the retina compared to the inner ear.

Mutation spectrum: The mutation spectrum of the USH1C gene includes a wide variety of pathogenic variants, such as missense, nonsense, frameshift, and splice-site mutations, as well as large deletions. These mutations are distributed throughout the gene, affecting different domains of the harmonin protein. Over 100 pathogenic variants have been reported in databases like ClinVar and HGMD. A notable feature of the USH1C mutation spectrum is the presence of founder mutations in specific populations. The most well-known is the c.216G>A (p.V72V) splice-site mutation, which is highly prevalent in the Acadian population of Louisiana and French Canadians in Quebec. This mutation creates a cryptic splice site, leading to a frameshift and premature truncation of the protein. Other founder mutations have also been identified in different ethnic groups, highlighting the importance of population-specific genetic screening.

Pathogenic variants: 1. c.216G>A (p.Val72=) - A synonymous variant that creates a cryptic splice site, leading to a frameshift and premature truncation. It is a major founder mutation in the Acadian and French Canadian populations, causing severe Usher syndrome type 1C. 2. c.238dupC (p.Arg80Profs*69) - A frameshift mutation resulting in a premature stop codon, leading to a loss of functional protein and causing Usher syndrome type 1C. 3. c.388G>A (p.Val130Ile) - A missense mutation located in the first PDZ domain of harmonin, affecting its ability to interact with other proteins and associated with Usher syndrome type 1C. 4. c.1000C>T (p.Arg334*) - A nonsense mutation that introduces a premature stop codon, resulting in a truncated, non-functional protein and causing Usher syndrome type 1C. 5. c.2200C>T (p.Arg734*) - Another nonsense mutation leading to premature truncation, associated with the severe Usher syndrome type 1C phenotype.

Clinical significance: Mutations in the USH1C gene primarily cause Usher syndrome type 1C (USH1C), an autosomal recessive disorder characterized by profound congenital sensorineural hearing loss, vestibular areflexia (balance issues), and progressive vision loss due to retinitis pigmentosa (RP). Infants with USH1C are typically born deaf and experience delayed motor milestones, such as walking, due to vestibular dysfunction. The vision loss in USH1C usually begins in childhood or early adolescence with night blindness (nyctalopia) and a progressive constriction of the visual field, eventually leading to legal blindness in adulthood. The severity and rate of progression of the retinal degeneration can vary among individuals, but it is generally considered one of the more severe forms of Usher syndrome. In rare cases, USH1C mutations have also been associated with non-syndromic autosomal recessive deafness (DFNB18), where patients experience hearing loss without the accompanying retinal degeneration or vestibular issues.

Inheritance: Autosomal recessive

Chromosomal location: 11p15.1

Genotype-phenotype correlations: Genotype-phenotype correlations in USH1C are complex and influenced by the specific type and location of the mutation, as well as the resulting effect on the different harmonin isoforms. Null mutations, such as nonsense or frameshift mutations that lead to a complete loss of functional harmonin protein, are generally associated with the classic, severe Usher syndrome type 1 phenotype, characterized by profound congenital deafness, vestibular dysfunction, and early-onset retinitis pigmentosa. Conversely, some missense mutations or splice-site variants that allow for the production of partially functional or specific isoforms of harmonin may result in a milder phenotype. For example, certain mutations have been linked to non-syndromic deafness (DFNB18), where the retinal function is preserved. The specific impact of a mutation on the various harmonin isoforms, which have distinct tissue distributions and functions, likely dictates whether the phenotype manifests as syndromic Usher syndrome or non-syndromic hearing loss.

Research and therapeutic approaches: Currently, there are no approved cures for the vision loss associated with USH1C. Management primarily focuses on supportive care, including cochlear implants for hearing loss, physical therapy for balance issues, and low-vision aids. However, several promising therapeutic approaches are in the preclinical and early clinical stages of development, aiming to slow or halt the progression of retinitis pigmentosa. Gene therapy is a major area of focus, utilizing viral vectors (such as AAV) to deliver a healthy copy of the USH1C gene to the retina. Preclinical studies in mouse and pig models have shown that gene replacement can successfully restore harmonin expression and improve retinal function. Another promising approach is the use of antisense oligonucleotides (ASOs), particularly for the c.216G>A founder mutation. ASOs are designed to bind to the mutated RNA and correct the splicing defect, allowing for the production of functional harmonin protein. This approach has shown significant efficacy in restoring hearing and vestibular function in mouse models and is being actively investigated for retinal applications.

Diagnostic testing: Diagnostic testing for USH1C mutations typically involves comprehensive genetic testing panels that sequence multiple genes associated with Usher syndrome and inherited retinal diseases. Next-generation sequencing (NGS) technologies, such as targeted gene panels or whole exome sequencing (WES), are commonly used to identify pathogenic variants in the USH1C gene. These tests can detect single nucleotide variants, small insertions/deletions, and sometimes larger copy number variations. Genetic counseling is highly recommended for individuals and families undergoing testing. It helps them understand the inheritance pattern (autosomal recessive), the implications of the test results for their health and family planning, and the potential risks for other family members. Prenatal testing and preimplantation genetic testing (PGT) are also options for families with known pathogenic USH1C variants.

Animal models: Animal models have been crucial for understanding USH1C function and developing therapies. The most prominent models are mouse knockouts and knock-ins, particularly those carrying the human c.216G>A (p.V72V) founder mutation. These mice exhibit profound deafness, vestibular dysfunction (circling behavior), and retinal abnormalities, closely mimicking the human phenotype. Zebrafish models have also been developed, demonstrating the requirement of harmonin for the development and maintenance of hair cells in the inner ear and photoreceptors in the retina. Recently, a transgenic pig model of USH1C has been generated, which provides a more anatomically and physiologically relevant model for human retinal disease compared to mice. This large animal model exhibits retinal degeneration and has been instrumental in testing the safety and efficacy of gene therapy and antisense oligonucleotide (ASO) approaches, paving the way for clinical translation.

Population genetics: The carrier frequency of USH1C mutations varies significantly among different populations. In the general population, Usher syndrome type 1 is relatively rare, with an estimated prevalence of about 1 in 45,000 to 1 in 65,000. However, USH1C mutations are notably more common in specific isolated populations due to founder effects. The most prominent example is the Acadian population in Louisiana (often referred to as Cajuns) and French Canadians in Quebec, where the c.216G>A founder mutation is highly prevalent. In these populations, the carrier frequency can be significantly higher than in the general population, making USH1C the leading cause of Usher syndrome in these groups.

Selected references: 1. Bitner-Glindzicz M, et al. A recessive contiguous gene deletion causing infantile hyperinsulinism, enteropathy and deafness identifies the Usher type 1C gene. Nat Genet. 2000. PMID: 11017082 2. Verpy E, et al. A defect in harmonin, a PDZ domain-containing protein expressed in the inner ear sensory hair cells, underlies Usher syndrome type 1C. Nat Genet. 2000. PMID: 11017083 3. Ebermann I, et al. Deafblindness in French Canadians from Quebec: a predominant founder mutation in the USH1C gene provides the first genetic link with the Acadian population. Hum Mutat. 2007. PMID: 17407589 4. Reiners J, et al. Scaffold protein harmonin (USH1C) provides molecular links between Usher syndrome type 1 and type 2. Hum Mol Genet. 2005. PMID: 16269440 5. Pan B, et al. Gene therapy restores auditory and vestibular function in a mouse model of Usher syndrome type 1c. Nat Biotechnol. 2017. PMID: 28165476 6. Géléoc GS, El-Amraoui A. Disease mechanisms and gene therapy for Usher syndrome. Hear Res. 2020. PMID: 32616330