Abstract
Xeroderma pigmentosum (XP) is a rare recessive heredity disease caused by DNA repair impairment characterized by photosensitivity and neurologic symptoms in half of the cases. There are eight subtypes of XP: XP-A–XP-G and XP variant. Among eight subtypes, XP complementation group A (XP-A) display the lowest DNA repair ability and the severest cutaneous and neurologic symptoms. While its pathogenesis of skin symptoms have been well-studied, that of neurological symptoms, including sensorineural hearing loss (SNHL) remains unknown. Basic studies have suggested that SNHL may be caused by inner ear damage, including damage to the spiral ganglion neurons and organ of Corti, and that the XP-A is associated with most severe form of SNHL in humans. Here, we report the occurrence of SNHL in Xpa-deficient mice. Xpa-deficient mice and wild-type mice underwent measurements for auditory brainstem response, and the results revealed that Xpa-deficient mice exhibited significantly greater (p < 0.01) ABR thresholds at 4, 8, and 16 kHz than the wild-type mice. Furthermore, the number of spiral ganglion neurons was reduced in Xpa-deficient mice compared with that in wild-type mice, indicating that hearing loss may be related to spiral ganglion neuron deficiency, consistent with the few reports published in human patients with XP. These results provide important insights into the pathogenesis of SNHL in patients with XP-A.
Highlights
Xeroderma pigmentosum (XP) is an autosomal recessive hereditary disease characterized by increased susceptibility to freckle-like pigmentation and skin cancers at sun-exposed body sites (DiGiovanna and Kraemer, 2012)
XP is classified into seven genetic complementation groups deficient in nucleotide excision repair (A through G) and an XP-variant type; the relative frequency and severity of cutaneous and neurological symptoms differ depending on the subtype
Humans are exposed to various genotoxic hazards; in order to protect the body from these hazards, its constituent cells have multiple pathways for repair of DNA damage caused by environmental agents, including endogenous factors such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), and exogenous factors such as UV radiation (UVR), ionizing radiation, electrophilic chemical adducts, and certain drugs
Summary
Xeroderma pigmentosum (XP) is an autosomal recessive hereditary disease characterized by increased susceptibility to freckle-like pigmentation and skin cancers at sun-exposed body sites (DiGiovanna and Kraemer, 2012). Humans are exposed to various genotoxic hazards; in order to protect the body from these hazards, its constituent cells have multiple pathways for repair of DNA damage caused by environmental agents, including endogenous factors such as reactive oxygen species (ROS) and reactive nitrogen species (RNS), and exogenous factors such as UV radiation (UVR), ionizing radiation, electrophilic chemical adducts, and certain drugs. If the DNA repair pathway fails to function properly, replication, and transcription errors occur, resulting in cell death and mutation. Patients with XP lack one of the NER protein complexes, and show an impaired capacity to properly repair DNA lesions that cause structural distortion, such as dipyrimidine photoproducts, which is caused by ultraviolet radiation (UVR), as well as DNA adducts caused by drugs (Cleaver, 2005). Several studies have shown that NER plays a partial role in repair of damage caused by ROS produced during endogenous metabolism (Menck and Munford, 2014)
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