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LOXHD1
lipoxygenase homology PLAT domains 1
LOXHD1 is located on the long (q) arm of chromosome 18, at band 18q21.1. Arm ratio per GRCh38 - banding schematic.
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Overview
LOXHD1 (lipoxygenase homology PLAT domains 1) is located on chromosome 18 at position 18q21.1 and encodes a 2,067 amino acid protein essential for auditory function. The gene was identified through genetic studies of families with hereditary hearing impairment, where linkage analysis revealed mutations segregating with hearing loss phenotypes. The LOXHD1 protein is predominantly expressed in the inner ear, specifically within the hair cells of the cochlea that detect sound waves. Disruption of this protein's normal function interferes with the delicate mechanosensory apparatus required for converting mechanical sound energy into neural signals, leading to progressive hearing impairment.
What the gene does
The LOXHD1 protein plays a structural and functional role within the stereocilia, the hair-like projections extending from cochlear hair cells that bend in response to sound vibrations. These stereocilia are organised in precise bundles, and their coordinated movement opens mechanosensitive ion channels that generate electrical signals transmitted to the auditory nerve. LOXHD1 is thought to contribute to maintaining the structural integrity of stereocilia and may participate in the molecular complexes that anchor components of the mechanotransduction machinery. The protein's multiple PLAT domains suggest involvement in membrane-associated functions or protein-lipid interactions, though the precise molecular mechanisms remain under investigation. Evidence suggests LOXHD1 may regulate stereocilia cohesion or the organisation of tip-link complexes that connect adjacent stereocilia, ensuring proper mechanical coupling during sound detection.
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Chromosome location
LOXHD1 is situated on the long arm of chromosome 18 at cytogenetic band 18q21.1. This chromosomal region contains multiple genes involved in diverse biological processes, though LOXHD1 itself shows restricted expression patterns with highest activity in cochlear tissues. The genomic structure of LOXHD1 spans a considerable length, reflecting its large coding sequence that produces the 2,067 amino acid protein product.
Protein structure
The LOXHD1 protein contains fifteen PLAT domains distributed across its length: PLAT 1 (amino acids 43-160), PLAT 2 (172-287), PLAT 3 (296-412), PLAT 4 (425-540), PLAT 5 (553-673), PLAT 6 (684-803), PLAT 7 (814-934), PLAT 8 (969-1087), PLAT 9 (1100-1225), PLAT 10 (1254-1372), PLAT 11 (1421-1539), PLAT 12 (1552-1667), PLAT 13 (1679-1797), PLAT 14 (1810-1931), and PLAT 15 (1948-2064). PLAT domains, also known as polycystin-1, lipoxygenase, alpha-toxin domains, are typically involved in membrane targeting or protein-protein interactions. The tandem arrangement of fifteen PLAT domains across the LOXHD1 protein creates an extended structure that may facilitate interactions with lipid membranes or other stereocilia components, potentially organising multi-protein complexes required for mechanotransduction.
Key variants
Pathogenic variants in LOXHD1 have been identified throughout the gene's coding sequence, including missense changes affecting individual PLAT domains, truncating mutations that eliminate portions of the protein, and splice-site alterations that disrupt normal transcript processing. The inheritance pattern associated with LOXHD1-related hearing loss can vary, with both autosomal recessive and digenic inheritance mechanisms reported in different families, reflecting genetic complexity in auditory disorders.
Sample of pathogenic variants
10 pathogenic / likely-pathogenic variants from ClinVar, ranked by review status (expert-panel-reviewed first). This is a sample; recurrent founder variants in a specific population may not appear here - see the full ClinVar listing via the link above.
| Variant (HGVS) | Protein change | Classification | Evidence | Associated condition |
|---|---|---|---|---|
c.246-1G>A | - | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 77 |
c.246-1G>T | - | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 77 |
c.4239C>A | p.Cys1413Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 77 |
c.4595_4605del | p.Asp1532fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 77 |
c.4832_4839dup | p.Thr1614delinsAlaGlnTer | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 77 |
c.488del | p.Phe163fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 77 |
c.6050-2A>C | - | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 77 |
c.6054C>A | p.Tyr2018Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 77 |
c.631G>T | p.Glu211Ter | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 77 |
c.6554_6555del | p.Thr2185fs | Pathogenic/Likely pathogenic | ★★☆☆ | Autosomal recessive nonsyndromic hearing loss 77 |
Evidence stars indicate ClinVar review status. Individual variant interpretation should always be performed by a qualified clinical laboratory - many variants remain classified as Variants of Uncertain Significance (VUS) pending more research.
Associated conditions
Variants in LOXHD1 are primarily associated with hereditary hearing loss, typically presenting as progressive sensorineural hearing impairment. The age of onset and severity can vary among affected individuals, with some experiencing hearing difficulties in early childhood whilst others develop symptoms during adolescence or young adulthood. The hearing loss often affects both ears symmetrically and may progress over time, though the rate of progression varies. Because hearing function depends on the coordinated activity of numerous genes, the phenotypic expression of LOXHD1 variants can be influenced by genetic background and environmental factors.
No disease links recorded for this gene in our reference set.
UK clinical status
LOXHD1 is included in the NHS Genomic Medicine Service Monogenic hearing loss panel (version R67) with a green rating, indicating sufficient evidence to support its use in clinical diagnostic testing for individuals with hereditary hearing impairment. This classification reflects confidence in the gene's clinical validity for identifying genetic causes of hearing loss in appropriate patient populations referred through NHS services.
Sources: NHS GMS PanelApp · Genomics England PanelApp · NHS National Genomic Test Directory
Frequently asked questions
What type of hearing loss is associated with LOXHD1 variants?
LOXHD1 variants typically cause sensorineural hearing loss, meaning the problem arises from dysfunction of the inner ear structures rather than issues with sound conduction through the outer or middle ear. The hearing impairment is often progressive and may begin in childhood or early adulthood.
How is LOXHD1-related hearing loss inherited?
LOXHD1-related hearing loss can follow different inheritance patterns depending on the specific variants involved. Most commonly it is inherited in an autosomal recessive manner, meaning two altered copies are needed for the condition to manifest, though more complex patterns have been reported in some families.
Is genetic testing for LOXHD1 available through the NHS?
Yes, LOXHD1 is included in the NHS Genomic Medicine Service panel for monogenic hearing loss with a green classification, indicating it is available for clinical diagnostic testing when hearing loss meets referral criteria established by NHS genomic services.