{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2025,10,11]],"date-time":"2025-10-11T01:36:59Z","timestamp":1760146619095,"version":"build-2065373602"},"reference-count":24,"publisher":"MDPI AG","issue":"12","license":[{"start":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T00:00:00Z","timestamp":1732492800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"limited internal resources from the Triangle Research and Development Center (TRDC)"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Genes"],"abstract":"<jats:p>Background\/Objectives: Biallelic mutations in the PTRH2 gene are associated with a rare genetic disease known as infantile-onset multisystem neurologic, endocrine, and pancreatic disease (IMNEPD). In this study, we describe a new case carrying a previously identified mutation, provide an updated analysis of the relative frequencies of the clinical features across all published cases (including the three latest studies), and perform a bioinformatics analysis of the newly identified PTRH2 protein variants from a structural perspective. Methods: Clinical examination of the patients was carried out, and genetic testing was performed using a genome sequencing strategy. A bioinformatics analysis was carried out for the newly reported mutations using PYMOL that was utilized to view the structure and analyze the mutations. Additionally, the ThermoMPNN webserver was employed to check the effect of point mutations on the overall stability of the protein. Results: Our findings indicate that motor delay, neuropathy, intellectual disability, distal weakness, hearing impairment, and ataxia are the most common symptoms, while the other clinical features fall into two frequency categories: moderately common ones and the least common ones. The bioinformatics analysis revealed that the Q85 residue is highly conserved, suggesting that mutations at this position could disrupt key signaling pathways or cellular functions. Indeed, the Q85R mutation was shown to significantly impair the stability and functionality of the protein. Conclusions: The clinical presentation of IMNEPD remains highly variable in terms of both severity and progression. Mutations at the Q85 residue have been identified in nearly 50% of reported cases, highlighting this position as a potential mutational hotspot in the PTRH2 protein.<\/jats:p>","DOI":"10.3390\/genes15121508","type":"journal-article","created":{"date-parts":[[2024,11,25]],"date-time":"2024-11-25T05:21:32Z","timestamp":1732512092000},"page":"1508","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["An Update of Phenotypic\u2013Genotypic IMNEPD Cases and a Bioinformatics Analysis of the New PTRH2 Gene Variants"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-0483-3443","authenticated-orcid":false,"given":"Rajech","family":"Sharkia","sequence":"first","affiliation":[{"name":"Unit of Human Biology and Genetics, The Triangle Regional Research and Development Center, Kafr Qari 3007500, Israel"},{"name":"Unit of Natural Sciences, Beit-Berl Academic College, Beit-Berl 4490500, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1080-972X","authenticated-orcid":false,"given":"Marie-Laure","family":"Vuillaume","sequence":"additional","affiliation":[{"name":"Genetics Department, Tours University Hospital, 37044 Tours, France"},{"name":"INSERM, Imaging Brain & Neuropsychiatry iBraiN U12523, University of Tours, 37032 Tours, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3799-2421","authenticated-orcid":false,"given":"Sahil","family":"Jain","sequence":"additional","affiliation":[{"name":"Bioinformatics Centre, Dr. D.Y. Patil Biotechnology and Bioinformatics Institute, Dr. D.Y. Patil Vidyapeeth, Pune 411033, India"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7818-8929","authenticated-orcid":false,"given":"Muhammad","family":"Mahajnah","sequence":"additional","affiliation":[{"name":"The Ruth and Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa 3109600, Israel"},{"name":"Child Neurology and Development Center, Hillel Yaffe Medical Center, Hadera 3810000, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Radka","family":"Stoeva","sequence":"additional","affiliation":[{"name":"Department of Medical Genetics, Le Mans Hospital, 72037 Le Mans, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Agn\u00e8s","family":"Guichet","sequence":"additional","affiliation":[{"name":"Genetics Department CHU 4 Rue Larrey, 49933 Angers, France"},{"name":"Miotvasc, UMR CNRS 6015, INSERM U1083, Angers University, 49933 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Estelle","family":"Colin","sequence":"additional","affiliation":[{"name":"Genetics Department CHU 4 Rue Larrey, 49933 Angers, France"},{"name":"Miotvasc, UMR CNRS 6015, INSERM U1083, Angers University, 49933 Angers, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"J\u00e9rome","family":"Champ","sequence":"additional","affiliation":[{"name":"SeqOIA Laboratory, FMG2025, 75014 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9804-5228","authenticated-orcid":false,"given":"Nicolas","family":"Derive","sequence":"additional","affiliation":[{"name":"SeqOIA Laboratory, FMG2025, 75014 Paris, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Arnaud","family":"Chefdor","sequence":"additional","affiliation":[{"name":"Department of Pediatrics, Le Mans Hospital, 72037 Le Mans, France"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4776-0675","authenticated-orcid":false,"given":"Abdelnaser","family":"Zalan","sequence":"additional","affiliation":[{"name":"Unit of Human Biology and Genetics, The Triangle Regional Research and Development Center, Kafr Qari 3007500, Israel"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2024,11,25]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1024","DOI":"10.1002\/acn3.149","article-title":"Mutations in PTRH2 Cause Novel Infantile-Onset Multisystem Disease with Intellectual Disability, Microcephaly, Progressive Ataxia, and Muscle Weakness","volume":"1","author":"Hu","year":"2014","journal-title":"Ann. 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