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TMPRSS3
transmembrane serine protease 3
TMPRSS3 is located on the long (q) arm of chromosome 21, at band 21q22.3. Arm ratio per GRCh38 - banding schematic.
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Overview
TMPRSS3 (transmembrane serine protease 3) is located on chromosome 21 and encodes a membrane-bound enzyme that belongs to the serine protease family. Serine proteases catalyse the cleavage of peptide bonds in proteins, a process fundamental to numerous biological pathways. The TMPRSS3 protein is particularly important in the cochlea, the spiral-shaped organ in the inner ear responsible for converting sound vibrations into electrical signals. Pathogenic variants in this gene disrupt normal cochlear function, leading to hearing impairment that typically presents from birth or early childhood. TMPRSS3-related hearing loss follows an autosomal recessive inheritance pattern, meaning affected individuals carry two variant copies of the gene.
What the gene does
The TMPRSS3 protein functions as a type II transmembrane serine protease, with its catalytic domain oriented towards the extracellular space. This positioning allows the enzyme to process substrates outside the cell or within the extracellular matrix. Within the cochlea, TMPRSS3 is expressed in specialised sensory cells and supporting structures, where it is thought to participate in protein maturation and turnover processes essential for auditory function. The precise molecular substrates of TMPRSS3 in the inner ear remain an active area of investigation, but evidence suggests the enzyme contributes to maintaining the ionic balance and structural integrity of the cochlear environment. Proper ionic homeostasis is critical for generating and transmitting auditory signals, and disruption of proteolytic processing may compromise the delicate cellular architecture required for hearing. The enzyme's activity appears particularly important during cochlear development and in the ongoing maintenance of hair cells, the sensory receptors that detect sound.
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Chromosome location
TMPRSS3 is located on the long arm of chromosome 21 at position 21q22.3. This chromosomal region contains several genes, and the TMPRSS3 gene itself spans a relatively compact genomic footprint. The gene produces a transcript that encodes a 454-amino-acid protein. Structural features of the genomic locus have been characterised through standard genome annotation efforts, though detailed exon-intron organisation varies across transcript isoforms.
Protein structure
The TMPRSS3 protein comprises 454 amino acids organised into distinct functional regions. The N-terminal portion contains an LDL-receptor class A domain spanning amino acids 72-108, which typically mediates protein-protein interactions and ligand binding. Adjacent to this is a SRCR domain (scavenger receptor cysteine-rich domain) from amino acids 109-205, a module found in proteins involved in immune response and cellular recognition processes. The catalytic region is formed by a Peptidase S1 domain extending from amino acids 217-449, which contains the characteristic serine protease catalytic triad responsible for enzymatic activity. This modular architecture allows the protein to anchor in membranes whilst positioning its protease activity appropriately for substrate recognition and cleavage in the extracellular environment.
Key variants
Pathogenic variants in TMPRSS3 are predominantly loss-of-function changes that reduce or abolish protease activity. Missense variants affecting the catalytic domain or critical structural residues, as well as nonsense and frameshift variants leading to truncated proteins, have been documented in individuals with hearing loss. The variant spectrum reflects the functional importance of the protease domain, with changes in this region typically associated with more severe auditory phenotypes. Carrier frequency varies across populations, with certain variants observed at higher rates in specific ancestries.
No pathogenic or likely-pathogenic ClinVar variants recorded yet for this gene.
Associated conditions
Variants in TMPRSS3 cause autosomal recessive non-syndromic hearing loss, most commonly classified as DFNB8 or DFNB10 depending on the genetic locus designation system. Affected individuals typically present with congenital or early-onset sensorineural hearing loss, ranging from moderate to profound severity. The hearing impairment is generally bilateral and non-progressive or slowly progressive, though phenotypic variability exists. Unlike syndromic forms of hearing loss, TMPRSS3-related hearing impairment occurs in isolation without other systemic features, distinguishing it from conditions affecting multiple organ systems.
No disease links recorded for this gene in our reference set.
UK clinical status
TMPRSS3 is included on the NHS Genomic Medicine Service Monogenic hearing loss panel with green classification, indicating strong evidence supporting its role in hereditary hearing impairment. This panel designation reflects the gene's clinical validity for diagnostic testing in individuals with unexplained hearing loss, particularly when family history or clinical presentation suggests a genetic cause.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What inheritance pattern does TMPRSS3-related hearing loss follow?
TMPRSS3-related hearing loss follows an autosomal recessive pattern, meaning an affected individual inherits one pathogenic variant from each parent. Parents who each carry one variant are typically unaffected but have a 25% chance with each pregnancy of having a child with two variants who may develop hearing loss.
Can TMPRSS3 variants cause hearing loss that appears later in life?
Most TMPRSS3-related hearing loss presents at birth or in early childhood, reflecting the gene's role in cochlear development and function. However, some variants may be associated with later onset or progressive hearing impairment, underscoring the phenotypic variability observed with different pathogenic changes.
Is genetic testing for TMPRSS3 available through the NHS?
Yes, TMPRSS3 is included on the NHS Genomic Medicine Service panel for monogenic hearing loss. Genetic testing may be offered to individuals with unexplained hearing impairment, particularly when clinical features suggest a genetic cause or when family history indicates recessive inheritance.