Charcot-Marie-Tooth type 1A disease caused by a novel Ser112Arg mutation in thePMP22 gene, coexisting with a slowly progressive hearing impairment

Kabzińska, Dagmara; Sinkiewicz–Darol, Elena; Hausmanowa-Pétrusewicz, I; Kochański, Andrzej

doi:10.1007/bf03195729

Cited by 3 publications

(3 citation statements)

References 18 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…A fourth gene, Plp1 , is implicated in Spastic paraplegia-2 and Pelizaeus-Merzbacher diseases [51], which are disorders closely related to ataxia. It is also a homologue of Pmp22 , which is involved in Charcot Marie Tooth disease type 1A, a sensory neuropathy common in some forms of ataxia [52]. Thus, even in the case of less well-studied phenotypes or diseases, our tissue-specific approach is able to identify likely candidates as evidenced by our success rate of at least 40% for ataxia-related predictions based on the cerebellar network, compared to a background detection rate of less than 1/500.…”

Section: Resultsmentioning

confidence: 99%

Tissue-Specific Functional Networks for Prioritizing Phenotype and Disease Genes

et al. 2012

View full text Add to dashboard Cite

Integrated analyses of functional genomics data have enormous potential for identifying phenotype-associated genes. Tissue-specificity is an important aspect of many genetic diseases, reflecting the potentially different roles of proteins and pathways in diverse cell lineages. Accounting for tissue specificity in global integration of functional genomics data is challenging, as “functionality” and “functional relationships” are often not resolved for specific tissue types. We address this challenge by generating tissue-specific functional networks, which can effectively represent the diversity of protein function for more accurate identification of phenotype-associated genes in the laboratory mouse. Specifically, we created 107 tissue-specific functional relationship networks through integration of genomic data utilizing knowledge of tissue-specific gene expression patterns. Cross-network comparison revealed significantly changed genes enriched for functions related to specific tissue development. We then utilized these tissue-specific networks to predict genes associated with different phenotypes. Our results demonstrate that prediction performance is significantly improved through using the tissue-specific networks as compared to the global functional network. We used a testis-specific functional relationship network to predict genes associated with male fertility and spermatogenesis phenotypes, and experimentally confirmed one top prediction, Mbyl1. We then focused on a less-common genetic disease, ataxia, and identified candidates uniquely predicted by the cerebellum network, which are supported by both literature and experimental evidence. Our systems-level, tissue-specific scheme advances over traditional global integration and analyses and establishes a prototype to address the tissue-specific effects of genetic perturbations, diseases and drugs.

show abstract

Section: Resultsmentioning

confidence: 99%

Tissue-Specific Functional Networks for Prioritizing Phenotype and Disease Genes

et al. 2012

View full text Add to dashboard Cite

show abstract

“…The auditory function deficits of CMT1A and CMT1E mice are profoundly different, but in each case are similar to those seen in patients with the respective mutations (32–35, 37–41, 68). Thus, we infer that it is likely that the cochlear structural phenotypes in each patient population correlate to those we see in each mouse model as well.…”

Section: Discussionmentioning

confidence: 70%

“…However, this has not been confirmed due to the lack of validated clinical HHL tests in humans (23,36). In contrast, patients with CMT1E, which is caused by a wide variety of PMP22 point mutations (29) and lead to more severe neuropathy phenotypes with earlier onset, suffer from overt hearing loss (elevated auditory thresholds) (37)(38)(39)(40)(41). Furthermore, a CMT1E mouse model, Trembler-J, has been shown to have profound deafness including AN fiber loss (42,43).…”

Section: Introductionmentioning

confidence: 99%

Hidden hearing loss in a Charcot-Marie-Tooth type 1A mouse model

Cassinotti,

Ji,

Yuk

et al. 2023

Preprint

View full text Add to dashboard Cite

Hidden hearing loss (HHL), a recently described auditory neuropathy characterized by normal audiometric thresholds but reduced sound evoked potentials, has been proposed to underlie hearing difficulties in noisy environments. Animal studies showing that HHL is associated with loss of inner hair cell (IHC) synapses in response to mild noise exposures and aging led to most studies of HHL focusing on IHC synaptopathy. More recently we showed that transient auditory nerve (AN) demyelination also causes HHL but without affecting IHC synapses, suggesting that demyelinating peripheral neuropathies could be a second HHL mechanism. To test this in a clinically relevant model, we studied a mouse model of Charcot-Marie-Tooth type 1A (CMT1A), the most prevalent hereditary peripheral neuropathy in humans. CMT1A mice exhibit HHL, i.e., normal auditory threshold but reduced amplitudes and longer latencies of sound-evoked compound action potential. The AN structural phenotypes of CMT1A mice are also remarkably similar to those found in mice with transient demyelination, i.e., disorganization of AN heminodes near the IHCs with minor loss of AN fibers. Our results support the hypothesis that mild disruptions of AN myelination can cause HHL, and that heminodal defects contribute to the alterations in action potential amplitudes and latencies seen in these models. Also, these findings suggest that patients with CMT1A or other peripheral neuropathies like Guillain-Barré Syndrome, are likely to suffer from HHL. Furthermore, these results suggest that studies of hearing in CMT1A patients might help in the development of robust clinical tests for HHL, which are currently lacking.Significance StatementHidden Hearing Loss (HHL), an auditory disorder estimated to affect 12-15% of the adult population, is believed to impact auditory processing and hearing clarity in individuals with normal audiometric thresholds. Based on animal studies, the loss of inner hair cell synapses is currently considered its primary cause. Here we provide evidence that mild disruptions of auditory nerve myelination, i.e., disorganization of auditory nerve heminodes, can also cause HHL. Our results suggest that patients suffering from Charcot-Marie-Tooth type 1A, the most common hereditary peripheral neuropathy, are likely to experience HHL. Studies of hearing in CMT1A patients might thus help in the development of robust clinical tests for HHL, which are currently lacking.

show abstract