CLRN1

CLRN1 (Clarin-1) is a gene located on chromosome 3q25.1 that encodes a transmembrane protein essential for hearing and vision, primarily expressed in cochlear hair cells and the retina. Mutations in CLRN1 are associated with Usher syndrome type IIIA (USH3A) and non-syndromic Retinitis Pigmentosa 61 (RP61), leading to progressive hearing loss and vision impairment.

What is CLRN1 (Clarin-1)?

CLRN1 is a gene, located on chromosome 3q25.1, that encodes Clarin-1. 

Clarin-1 is a transmembrane protein essential for hearing and vision, primarily expressed in cochlear hair cells and the retina. It plays a key role in F-actin organization, synaptic stability, and intracellular trafficking.

Mutations in CLRN1 cause Usher syndrome type IIIA (USH3A), an autosomal recessive disorder leading to progressive hearing loss, retinitis pigmentosa, and variable vestibular dysfunction. Some variants are also linked to non-syndromic Retinitis Pigmentosa 61 (RP61).

Understanding CLRN1’s role in synaptic and cytoskeletal stability may guide future therapeutic strategies for Usher syndrome and related disorders.

Key Pathogenic Mutations

• N48K Mutation (common in Ashkenazi Jewish populations): Disrupts glycosylation, leading to protein misfolding and degradation.

• Other mutations (missense, nonsense, deletions): Lead to loss of function and progressive sensory impairment.

Conditions Associated with CLRN1 Mutations

Patients with progressive hearing and vision loss should be screened for CLRN1 mutations, especially in high-risk populations.

Usher Syndrome Type IIIA (USH3A)

Usher Syndrome consists of various manifestations of this cluster of symptoms:

Usher Syndrome Overview

Usher syndrome is an autosomal recessive disorder that is the leading cause of deaf-blindness globally.

It is classified into three primary types (I, II, III) based on the severity and progression of hearing loss, vision impairment (retinitis pigmentosa, RP), and vestibular dysfunction.

Type 3A Features

Usher syndrome type 3A (USH3A) is progressive, with hearing loss that begins postnatally (after speech development), distinguishing it from types I and II.

Visual symptoms due to retinitis pigmentosa (RP) develop within the first few decades of life and progress more rapidly than in type II.

Vestibular dysfunction in USH3A is variable and not as severe as in type I.

Non-Syndromic Retinitis Pigmentosa 61 (RP61)

Non-Syndromic Retinitis Pigmentosa 61 (RP61) is a rare inherited retinal disorder caused by mutations in the CLRN1 gene, leading to progressive degeneration of photoreceptors. It primarily affects night vision, followed by gradual loss of peripheral and central vision due to retinal atrophy. 

RP61 follows an autosomal recessive inheritance pattern, and while no cure exists, genetic testing can aid in diagnosis and risk assessment for affected families.

Who Should Get CLRN1 Testing?

The following groups of people may consider CLRN1 genetic testing:

Individuals with Symptoms of Usher Syndrome Type IIIA (USH3A)

Symptoms include:

• Progressive postnatal hearing loss (sensorineural, usually beginning after speech development)
• Vision impairment due to retinitis pigmentosa (RP), often appearing in the first few decades of life
• Variable vestibular dysfunction (balance issues, dizziness, or difficulty with coordination)
• Individuals from high-risk populations, such as those of Ashkenazi Jewish descent, due to the N48K mutation

Individuals with Symptoms of Non-Syndromic Retinitis Pigmentosa 61 (RP61)

Symptoms include:

• Progressive night blindness (nyctalopia)
• Peripheral vision loss leading to tunnel vision
• Gradual central vision decline due to photoreceptor degeneration
• Family history of autosomal recessive RP without hearing loss

Infants or Children with Hearing or Vision Concerns

• Children with progressive hearing loss of unknown cause, especially if postnatal onset
• Early-onset visual impairment or family history of inherited retinal disease

Individuals with a Family History of CLRN1-Related Disorders

• First-degree relatives of individuals diagnosed with USH3A or RP61
• Families with multiple cases of hearing loss and/or vision impairment suggestive of recessive inheritance

Prenatal and Carrier Screening for At-Risk Populations

• Individuals with Ashkenazi Jewish ancestry considering family planning, due to the higher prevalence of the N48K mutation
• Couples with a family history of Usher syndrome or RP who wish to assess carrier status
• Prospective parents undergoing expanded genetic carrier screening

Patients Undergoing Genetic Testing for Retinal Degeneration or Hearing Loss

• Individuals undergoing comprehensive genetic panels for inherited eye diseases or hearing loss disorders

Test Procedure and Interpretation

The following section outlines the testing procedures and interpretation.

Testing Procedure and Preparation

Genetic testing involves blood, saliva, or cheek swab samples, although specialized laboratories may recommend different sample types. 

A cheek swab or saliva sample is easily obtained from the comfort of home, while blood samples typically require a blood draw.

Normal Reference Ranges

Normal reference ranges for CLRN1 genetic testing are considered to be without mutations that can alter the activity of the CLRN1 proteins.

Clinical Implications of Positive CLRN1 Mutations

The clinical implications of a positive CLRN1 mutation test result will vary by individual, although CLRN1 mutations in symptomatic patients may signal a need for further assessment and possibly treatment, especially in the setting of cancer and/or progressive hearing loss. 

Patients or practitioners with questions about the clinical implications of CLRN1 mutations should seek further assessment with a genetic counselor or expert. 

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