Missense variant in LOXHD1 is associated with canine nonsyndromic hearing loss

Hytönen, Marjo K.; Niskanen, Julia E.; Arumilli, Meharji; Brookhart-Knox, Casey A.; Donner, Jonas; Lohi, Hannes

doi:10.1007/s00439-021-02286-z

Cited by 6 publications

(4 citation statements)

References 44 publications

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“…Mutations in the gene LOXHD1 cause recessive hearing loss in Humans (DFNB77), mouse and dogs [39][40][41][42][43] but is molecular function remains elusive. LOXHD1 is composed of up to 15 PLAT (polycystin lipoxygenase alpha-toxin) repeats and one coiled-coil domain 39 .…”

Section: A Large-scale Genomic Deletion Of Loxhd1 In Mice Leads To Se...mentioning

confidence: 99%

LOXHD1 is indispensable for coupling auditory mechanosensitive channels to the site of force transmission

Wang,

Miller,

et al. 2024

Preprint

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Hearing is initiated in hair cells by the mechanical activation of ion channels in the hair bundle. The hair bundle is formed by stereocilia organized into rows of increasing heights interconnected by tip links, which convey sound-induced forces to stereocilia tips. The auditory mechanosensitive channels are complexes containing at least four protein-subunits – TMC1/2, TMIE, CIB2, and LHFPL5 – and are located at the tips of shorter stereocilia at a yet-undetermined distance from the lower tip link insertion point. While multiple auditory channel subunits appear to interact with the tip link, it remains unknown whether their combined interaction alone can resist the high-frequency mechanical stimulations owing to sound. Here we show that an unanticipated additional element, LOXHD1, is indispensable for maintaining the TMC1 pore-forming channel subunits coupled to the tip link. We demonstrate that LOXHD1 is a unique element of the auditory mechanotransduction complex that selectively affects the localization of TMC1, but not its close developmental paralogue TMC2. Taking advantage of our novel immunogold scanning electron microscopy method for submembranous epitopes (SUB-immunogold-SEM), we demonstrate that TMC1 normally concentrates within 100-nm of the tip link insertion point. In LOXHD1’s absence, TMC1 is instead mislocalized away from this force transmission site. Supporting this finding, we found that LOXHD1 interacts selectively in vitro with TMC1 but not with TMC2 while also binding to channel subunits CIB2 and LHFPL5 and tip-link protein PCDH15. SUB-immunogold-SEM additionally demonstrates that LOXHD1 and TMC1 are physically connected to the lower tip-link complex in situ. Our results show that the TMC1-driven mature channels require LOXHD1 to stay coupled to the tip link and remain functional, but the TMC2-driven developmental channels do not. As both tip links and TMC1 remain present in hair bundles lacking LOXHD1, it opens the possibility to reconnect them and restore hearing for this form of genetic deafness.

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Section: A Large-scale Genomic Deletion Of Loxhd1 In Mice Leads To Se...mentioning

confidence: 99%

LOXHD1 is indispensable for coupling auditory mechanosensitive channels to the site of force transmission

Wang,

Miller,

et al. 2024

Preprint

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“…The associated variant was a 12 bp deletion in the EPS8L2 gene [143]. In Rottweilers, sensorineural bilateral deafness with onset at a few weeks of age was associated with a missense variant in the LOXHD1 gene [144].…”

Section: Deafnessmentioning

confidence: 99%

An Overview of Canine Inherited Neurological Disorders with Known Causal Variants

Cocostîrc,

Paștiu,

Pusta

2023

Animals

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Hereditary neurological conditions documented in dogs encompass congenital, neonatal, and late-onset disorders, along with both progressive and non-progressive forms. In order to identify the causal variant of a disease, the main two approaches are genome-wide investigations and candidate gene investigation. Online Mendelian Inheritance in Animals currently lists 418 Mendelian disorders specific to dogs, of which 355 have their likely causal genetic variant identified. This review aims to summarize the current knowledge on the canine nervous system phenes and their genetic causal variant. It has been noted that the majority of these diseases have an autosomal recessive pattern of inheritance. Additionally, the dog breeds that are more prone to develop such diseases are the Golden Retriever, in which six inherited neurological disorders with a known causal variant have been documented, and the Belgian Shepherd, in which five such disorders have been documented. DNA tests can play a vital role in effectively managing and ultimately eradicating inherited diseases.

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“…Nonsyndromic hearing loss is a significant medical problem in many breeds of dogs, yet the genetic bases have remained elusive. In this issue of Human Genetics, Hytönen et al (2021a) identify a missense variant in LOXHD1 in the Rottweiler dog, a gene that is known to be essential for cochlear hair cell function. This gene contributes to hearing loss in humans and mice, and represents the first identified variant for nonsyndromic hearing loss in dogs.…”

Section: Novel Findings Identified For Inherited Diseases In Dogsmentioning

confidence: 99%

Special issue on companion animal genetics: Novel variants discovered in wide variety of diseases in dogs, identification and further characterization of traits in dogs and cats, and the use of microarrays in the detection of aneuploidy in dogs

Shaffer

2021

Hum Genet

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Missense variant in LOXHD1 is associated with canine nonsyndromic hearing loss

Cited by 6 publications

References 44 publications

LOXHD1 is indispensable for coupling auditory mechanosensitive channels to the site of force transmission

LOXHD1 is indispensable for coupling auditory mechanosensitive channels to the site of force transmission

An Overview of Canine Inherited Neurological Disorders with Known Causal Variants

Special issue on companion animal genetics: Novel variants discovered in wide variety of diseases in dogs, identification and further characterization of traits in dogs and cats, and the use of microarrays in the detection of aneuploidy in dogs

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