Deficiency in the endocytic adaptor proteins PHETA1/2 impair renal and craniofacial development
<p dir="ltr">A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain containing endocytic traf...
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2020
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| author | Kristin M. Ates (18949450) |
| author2 | Tong Wang (87696) Trevor Moreland (18949453) Rajalakshmi Veeranan-Karmegam (10707960) Manxiu Ma (8347386) Chelsi Jeter (18949456) Priya Anand (6838310) Wolfgang Wenzel (25116) Hyung-Goo Kim (728597) Lynne A. Wolfe (18949459) Joshi A. Stephen (18949462) David R. Adams (2135944) Thomas Markello (202566) Cynthia J. Tifft (8981177) Robert Settlage (751097) William A. Gahl (169534) Graydon B. Gonsalvez (10707963) May Christine Malicdan (5229317) Heather Flanagan-Steet (18949465) Y. Albert Pan (8347389) |
| author2_role | author author author author author author author author author author author author author author author author author author author |
| author_facet | Kristin M. Ates (18949450) Tong Wang (87696) Trevor Moreland (18949453) Rajalakshmi Veeranan-Karmegam (10707960) Manxiu Ma (8347386) Chelsi Jeter (18949456) Priya Anand (6838310) Wolfgang Wenzel (25116) Hyung-Goo Kim (728597) Lynne A. Wolfe (18949459) Joshi A. Stephen (18949462) David R. Adams (2135944) Thomas Markello (202566) Cynthia J. Tifft (8981177) Robert Settlage (751097) William A. Gahl (169534) Graydon B. Gonsalvez (10707963) May Christine Malicdan (5229317) Heather Flanagan-Steet (18949465) Y. Albert Pan (8347389) |
| author_role | author |
| dc.creator.none.fl_str_mv | Kristin M. Ates (18949450) Tong Wang (87696) Trevor Moreland (18949453) Rajalakshmi Veeranan-Karmegam (10707960) Manxiu Ma (8347386) Chelsi Jeter (18949456) Priya Anand (6838310) Wolfgang Wenzel (25116) Hyung-Goo Kim (728597) Lynne A. Wolfe (18949459) Joshi A. Stephen (18949462) David R. Adams (2135944) Thomas Markello (202566) Cynthia J. Tifft (8981177) Robert Settlage (751097) William A. Gahl (169534) Graydon B. Gonsalvez (10707963) May Christine Malicdan (5229317) Heather Flanagan-Steet (18949465) Y. Albert Pan (8347389) |
| dc.date.none.fl_str_mv | 2020-05-26T12:00:00Z |
| dc.identifier.none.fl_str_mv | 10.1242/dmm.041913 |
| dc.relation.none.fl_str_mv | https://figshare.com/articles/journal_contribution/Deficiency_in_the_endocytic_adaptor_proteins_PHETA1_2_impair_renal_and_craniofacial_development/26144098 |
| dc.rights.none.fl_str_mv | CC BY 4.0 info:eu-repo/semantics/openAccess |
| dc.subject.none.fl_str_mv | Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Neurosciences PHETA1 IPIP27A OCRL Endocytosis Undiagnosed disease |
| dc.title.none.fl_str_mv | Deficiency in the endocytic adaptor proteins PHETA1/2 impair renal and craniofacial development |
| dc.type.none.fl_str_mv | Text Journal contribution info:eu-repo/semantics/publishedVersion text contribution to journal |
| description | <p dir="ltr">A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain containing endocytic trafficking adaptor 1 and 2 (PHETA1/2, also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, pheta1 and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentations of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient.</p><h2>Other Information</h2><p dir="ltr">Published in: Disease Models & Mechanisms<br>License: <a href="http://creativecommons.org/licenses/by/4.0" target="_blank">http://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1242/dmm.041913" target="_blank">https://dx.doi.org/10.1242/dmm.041913</a></p> |
| eu_rights_str_mv | openAccess |
| id | Manara2_7685475cf5f4e2df685590598c81d637 |
| identifier_str_mv | 10.1242/dmm.041913 |
| network_acronym_str | Manara2 |
| network_name_str | Manara2 |
| oai_identifier_str | oai:figshare.com:article/26144098 |
| publishDate | 2020 |
| repository.mail.fl_str_mv | |
| repository.name.fl_str_mv | |
| repository_id_str | |
| rights_invalid_str_mv | CC BY 4.0 |
| spelling | Deficiency in the endocytic adaptor proteins PHETA1/2 impair renal and craniofacial developmentKristin M. Ates (18949450)Tong Wang (87696)Trevor Moreland (18949453)Rajalakshmi Veeranan-Karmegam (10707960)Manxiu Ma (8347386)Chelsi Jeter (18949456)Priya Anand (6838310)Wolfgang Wenzel (25116)Hyung-Goo Kim (728597)Lynne A. Wolfe (18949459)Joshi A. Stephen (18949462)David R. Adams (2135944)Thomas Markello (202566)Cynthia J. Tifft (8981177)Robert Settlage (751097)William A. Gahl (169534)Graydon B. Gonsalvez (10707963)May Christine Malicdan (5229317)Heather Flanagan-Steet (18949465)Y. Albert Pan (8347389)Biological sciencesBiochemistry and cell biologyGeneticsBiomedical and clinical sciencesNeurosciencesPHETA1IPIP27AOCRLEndocytosisUndiagnosed disease<p dir="ltr">A critical barrier in the treatment of endosomal and lysosomal diseases is the lack of understanding of the in vivo functions of the putative causative genes. We addressed this by investigating a key pair of endocytic adaptor proteins, PH domain containing endocytic trafficking adaptor 1 and 2 (PHETA1/2, also known as FAM109A/B, Ses1/2, IPIP27A/B), which interact with the protein product of OCRL, the causative gene for Lowe syndrome. Here we conducted the first study of PHETA1/2 in vivo, utilizing the zebrafish system. We found that impairment of both zebrafish orthologs, pheta1 and pheta2, disrupted endocytosis and ciliogenesis in renal tissues. In addition, pheta1/2 mutant animals exhibited reduced jaw size and delayed chondrocyte differentiation, indicating a role in craniofacial development. Deficiency of pheta1/2 resulted in dysregulation of cathepsin K, which led to an increased abundance of type II collagen in craniofacial cartilages, a marker of immature cartilage extracellular matrix. Cathepsin K inhibition rescued the craniofacial phenotypes in the pheta1/2 double mutants. The abnormal renal and craniofacial phenotypes in the pheta1/2 mutant animals were consistent with the clinical presentations of a patient with a de novo arginine (R) to cysteine (C) variant (R6C) of PHETA1. Expressing the patient-specific variant in zebrafish exacerbated craniofacial deficits, suggesting that the R6C allele acts in a dominant-negative manner. Together, these results provide insights into the in vivo roles of PHETA1/2 and suggest that the R6C variant is contributory to the pathogenesis of disease in the patient.</p><h2>Other Information</h2><p dir="ltr">Published in: Disease Models & Mechanisms<br>License: <a href="http://creativecommons.org/licenses/by/4.0" target="_blank">http://creativecommons.org/licenses/by/4.0</a><br>See article on publisher's website: <a href="https://dx.doi.org/10.1242/dmm.041913" target="_blank">https://dx.doi.org/10.1242/dmm.041913</a></p>2020-05-26T12:00:00ZTextJournal contributioninfo:eu-repo/semantics/publishedVersiontextcontribution to journal10.1242/dmm.041913https://figshare.com/articles/journal_contribution/Deficiency_in_the_endocytic_adaptor_proteins_PHETA1_2_impair_renal_and_craniofacial_development/26144098CC BY 4.0info:eu-repo/semantics/openAccessoai:figshare.com:article/261440982020-05-26T12:00:00Z |
| spellingShingle | Deficiency in the endocytic adaptor proteins PHETA1/2 impair renal and craniofacial development Kristin M. Ates (18949450) Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Neurosciences PHETA1 IPIP27A OCRL Endocytosis Undiagnosed disease |
| status_str | publishedVersion |
| title | Deficiency in the endocytic adaptor proteins PHETA1/2 impair renal and craniofacial development |
| title_full | Deficiency in the endocytic adaptor proteins PHETA1/2 impair renal and craniofacial development |
| title_fullStr | Deficiency in the endocytic adaptor proteins PHETA1/2 impair renal and craniofacial development |
| title_full_unstemmed | Deficiency in the endocytic adaptor proteins PHETA1/2 impair renal and craniofacial development |
| title_short | Deficiency in the endocytic adaptor proteins PHETA1/2 impair renal and craniofacial development |
| title_sort | Deficiency in the endocytic adaptor proteins PHETA1/2 impair renal and craniofacial development |
| topic | Biological sciences Biochemistry and cell biology Genetics Biomedical and clinical sciences Neurosciences PHETA1 IPIP27A OCRL Endocytosis Undiagnosed disease |