The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model
Most human disease manifests as a result of tissue pathology, due to an underlying disease process (pathogenesis), rather than the acute loss of specific molecular function(s). Successful therapeutic strategies thus may either target the correction of a specific molecular function or halt the diseas...
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MDPI AG
2022-03-01
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| Online Access: | https://www.mdpi.com/2073-4409/11/7/1131 |
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| author | Konark Mukherjee Leslie E. W. LaConte Sarika Srivastava |
| author_facet | Konark Mukherjee Leslie E. W. LaConte Sarika Srivastava |
| author_sort | Konark Mukherjee |
| collection | DOAJ |
| description | Most human disease manifests as a result of tissue pathology, due to an underlying disease process (pathogenesis), rather than the acute loss of specific molecular function(s). Successful therapeutic strategies thus may either target the correction of a specific molecular function or halt the disease process. For the vast majority of brain diseases, clear etiologic and pathogenic mechanisms are still elusive, impeding the discovery or design of effective disease-modifying drugs. The development of valid animal models and their proper characterization is thus critical for uncovering the molecular basis of the underlying pathobiological processes of brain disorders. MICPCH (microcephaly and pontocerebellar hypoplasia) is a monogenic condition that results from variants of an X-linked gene, <i>CASK</i> (calcium/calmodulin-dependent serine protein kinase). <i>CASK</i> variants are associated with a wide range of clinical presentations, from lethality and epileptic encephalopathies to intellectual disabilities, microcephaly, and autistic traits. We have examined <i>CASK</i> loss-of-function mutations in model organisms to simultaneously understand the pathogenesis of MICPCH and the molecular function/s of CASK. Our studies point to a highly complex relationship between the potential molecular function/s of <i>CASK</i> and the phenotypes observed in model organisms and humans. Here we discuss the implications of our observations from the pathogenesis of MICPCH as a cautionary narrative against oversimplifying molecular interpretations of data obtained from genetically modified animal models of human diseases. |
| first_indexed | 2024-03-09T12:01:01Z |
| format | Article |
| id | doaj.art-c68b082e5531430bad98b8f48e8a4062 |
| institution | Directory Open Access Journal |
| issn | 2073-4409 |
| language | English |
| last_indexed | 2024-03-09T12:01:01Z |
| publishDate | 2022-03-01 |
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| spelling | doaj.art-c68b082e5531430bad98b8f48e8a40622023-11-30T23:03:55ZengMDPI AGCells2073-44092022-03-01117113110.3390/cells11071131The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse ModelKonark Mukherjee0Leslie E. W. LaConte1Sarika Srivastava2Fralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USAFralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USAFralin Biomedical Research Institute at VTC, Roanoke, VA 24016, USAMost human disease manifests as a result of tissue pathology, due to an underlying disease process (pathogenesis), rather than the acute loss of specific molecular function(s). Successful therapeutic strategies thus may either target the correction of a specific molecular function or halt the disease process. For the vast majority of brain diseases, clear etiologic and pathogenic mechanisms are still elusive, impeding the discovery or design of effective disease-modifying drugs. The development of valid animal models and their proper characterization is thus critical for uncovering the molecular basis of the underlying pathobiological processes of brain disorders. MICPCH (microcephaly and pontocerebellar hypoplasia) is a monogenic condition that results from variants of an X-linked gene, <i>CASK</i> (calcium/calmodulin-dependent serine protein kinase). <i>CASK</i> variants are associated with a wide range of clinical presentations, from lethality and epileptic encephalopathies to intellectual disabilities, microcephaly, and autistic traits. We have examined <i>CASK</i> loss-of-function mutations in model organisms to simultaneously understand the pathogenesis of MICPCH and the molecular function/s of CASK. Our studies point to a highly complex relationship between the potential molecular function/s of <i>CASK</i> and the phenotypes observed in model organisms and humans. Here we discuss the implications of our observations from the pathogenesis of MICPCH as a cautionary narrative against oversimplifying molecular interpretations of data obtained from genetically modified animal models of human diseases.https://www.mdpi.com/2073-4409/11/7/1131CASKMICPCHpontocerebellar hypoplasiapathogenesis |
| spellingShingle | Konark Mukherjee Leslie E. W. LaConte Sarika Srivastava The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model Cells CASK MICPCH pontocerebellar hypoplasia pathogenesis |
| title | The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model |
| title_full | The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model |
| title_fullStr | The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model |
| title_full_unstemmed | The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model |
| title_short | The Non-Linear Path from Gene Dysfunction to Genetic Disease: Lessons from the MICPCH Mouse Model |
| title_sort | non linear path from gene dysfunction to genetic disease lessons from the micpch mouse model |
| topic | CASK MICPCH pontocerebellar hypoplasia pathogenesis |
| url | https://www.mdpi.com/2073-4409/11/7/1131 |
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