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TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis
Background. Mutations in the TRPC6 gene have been reported in six families with adult-onset (17–57 years) autosomal dominant focal segmental glomerulosclerosis (FSGS). Electrophysiology studies confirmed augmented calcium influx only in three of these six TRPC6 mutations. To date, the role of TRPC6...
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| Published in: | Nephrology, dialysis, transplantation dialysis, transplantation, 2009-10, Vol.24 (10), p.3089-3096 |
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| creator | Santín, Sheila Ars, Elisabet Rossetti, Sandro Salido, Eduardo Silva, Irene García-Maset, Rafael Giménez, Isabel Ruíz, Patricia Mendizábal, Santiago Luciano Nieto, José Peña, Antonia Camacho, Juan Antonio Fraga, Gloria Cobo, Mª Ángeles Bernis, Carmen Ortiz, Alberto de Pablos, Augusto Luque Sánchez-Moreno, Ana Pintos, Guillem Mirapeix, Eduard Fernández-Llama, Patricia Ballarín, José Torra, Roser |
| description | Background. Mutations in the TRPC6 gene have been reported in six families with adult-onset (17–57 years) autosomal dominant focal segmental glomerulosclerosis (FSGS). Electrophysiology studies confirmed augmented calcium influx only in three of these six TRPC6 mutations. To date, the role of TRPC6 in childhood and adulthood non-familial forms is unknown. Methods. TRPC6 mutation analysis was performed by direct sequencing in 130 Spanish patients from 115 unrelated families with FSGS. An in silico scoring matrix was developed to evaluate the pathogenicity of amino acid substitutions, by using the bio-physical and bio-chemical differences between wild-type and mutant amino acid, the evolutionary conservation of the amino acid residue in orthologues, homologues and defined domains, with the addition of contextual information. Results. Three new missense substitutions were identified in two clinically non-familial cases and in one familial case. The analysis by means of this scoring system allowed us to classify these variants as likely pathogenic mutations. One of them was detected in a female patient with unusual clinical features: mesangial proliferative FSGS in childhood (7 years) and partial response to immunosupressive therapy (CsA + MMF). Asymptomatic carriers of this likely mutation were found within her family. Conclusions. We describe for the first time TRPC6 mutations in children and adults with non-familial FSGS. It seems that TRPC6 is a gene with a very variable penetrance that may contribute to glomerular diseases in a multi-hit setting. |
| doi_str_mv | 10.1093/ndt/gfp229 |
| format | article |
| fullrecord | <record><control><sourceid>proquest_cross</sourceid><recordid>TN_cdi_proquest_miscellaneous_734054841</recordid><sourceformat>XML</sourceformat><sourcesystem>PC</sourcesystem><oup_id>10.1093/ndt/gfp229</oup_id><sourcerecordid>21119997</sourcerecordid><originalsourceid>FETCH-LOGICAL-c415t-f7452860a9d67aedd7989873d2a79383a426d5e7d5be60161e669cb954bdeeb3</originalsourceid><addsrcrecordid>eNp90E9rFDEYBvAgit1WL34AyUUFYWz-Z3KUwbbCokUXFC8hM3lnOzozGZMM2m9vZJf21ksSkl-ekAehF5S8o8Tw89nn832_MGYeoQ0VilSM1_Ix2pRDWhFJzAk6TeknIcQwrZ-iE2qErIkiG2R3X64bhac1uzyE2Y3YleE2DQkPM3Z4dHEPuAs3IWYcerwUBnNO-M-Qb3AfunIjwX4qe2W1H8MEcR1D6kaIoaQ8Q096NyZ4fpzP0O7iw665qrafLz8277dVJ6jMVa-FZLUiznilHXivTW1qzT1z2vCaO8GUl6C9bEERqigoZbrWSNF6gJafoTeH2CWG3yukbKchdTCOboawJqu5IFLUghb5-kHJKKXGGF3g2wPsykdShN4ucZhcvLWU2P-929K7PfRe8Mtj6tpO4O_psegCXh2BS6WzPrq5G9KdY4xQrgW7d2FdHn6wOrghZfh7J138ZZXmWtqr7z9sc_3t4mtTf7Jb_g97oahr</addsrcrecordid><sourcetype>Aggregation Database</sourcetype><iscdi>true</iscdi><recordtype>article</recordtype><pqid>21119997</pqid></control><display><type>article</type><title>TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis</title><source>Oxford University Press</source><creator>Santín, Sheila ; Ars, Elisabet ; Rossetti, Sandro ; Salido, Eduardo ; Silva, Irene ; García-Maset, Rafael ; Giménez, Isabel ; Ruíz, Patricia ; Mendizábal, Santiago ; Luciano Nieto, José ; Peña, Antonia ; Camacho, Juan Antonio ; Fraga, Gloria ; Cobo, Mª Ángeles ; Bernis, Carmen ; Ortiz, Alberto ; de Pablos, Augusto Luque ; Sánchez-Moreno, Ana ; Pintos, Guillem ; Mirapeix, Eduard ; Fernández-Llama, Patricia ; Ballarín, José ; Torra, Roser</creator><creatorcontrib>Santín, Sheila ; Ars, Elisabet ; Rossetti, Sandro ; Salido, Eduardo ; Silva, Irene ; García-Maset, Rafael ; Giménez, Isabel ; Ruíz, Patricia ; Mendizábal, Santiago ; Luciano Nieto, José ; Peña, Antonia ; Camacho, Juan Antonio ; Fraga, Gloria ; Cobo, Mª Ángeles ; Bernis, Carmen ; Ortiz, Alberto ; de Pablos, Augusto Luque ; Sánchez-Moreno, Ana ; Pintos, Guillem ; Mirapeix, Eduard ; Fernández-Llama, Patricia ; Ballarín, José ; Torra, Roser ; FSGS Study Group ; on behalf of the FSGS Study Group</creatorcontrib><description>Background. Mutations in the TRPC6 gene have been reported in six families with adult-onset (17–57 years) autosomal dominant focal segmental glomerulosclerosis (FSGS). Electrophysiology studies confirmed augmented calcium influx only in three of these six TRPC6 mutations. To date, the role of TRPC6 in childhood and adulthood non-familial forms is unknown. Methods. TRPC6 mutation analysis was performed by direct sequencing in 130 Spanish patients from 115 unrelated families with FSGS. An in silico scoring matrix was developed to evaluate the pathogenicity of amino acid substitutions, by using the bio-physical and bio-chemical differences between wild-type and mutant amino acid, the evolutionary conservation of the amino acid residue in orthologues, homologues and defined domains, with the addition of contextual information. Results. Three new missense substitutions were identified in two clinically non-familial cases and in one familial case. The analysis by means of this scoring system allowed us to classify these variants as likely pathogenic mutations. One of them was detected in a female patient with unusual clinical features: mesangial proliferative FSGS in childhood (7 years) and partial response to immunosupressive therapy (CsA + MMF). Asymptomatic carriers of this likely mutation were found within her family. Conclusions. We describe for the first time TRPC6 mutations in children and adults with non-familial FSGS. It seems that TRPC6 is a gene with a very variable penetrance that may contribute to glomerular diseases in a multi-hit setting.</description><identifier>ISSN: 0931-0509</identifier><identifier>EISSN: 1460-2385</identifier><identifier>DOI: 10.1093/ndt/gfp229</identifier><identifier>PMID: 19458060</identifier><identifier>CODEN: NDTREA</identifier><language>eng</language><publisher>Oxford: Oxford University Press</publisher><subject>Adolescent ; Adult ; Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy ; Biological and medical sciences ; Child ; Child, Preschool ; DNA Mutational Analysis ; Emergency and intensive care: renal failure. Dialysis management ; Female ; focal segmental glomerulosclerosis ; Glomerulonephritis ; Glomerulosclerosis, Focal Segmental - genetics ; Humans ; in silico scoring system ; Infant ; Intensive care medicine ; Medical sciences ; Middle Aged ; missense substitutions ; mutation analysis ; Nephrology. Urinary tract diseases ; Nephropathies. Renovascular diseases. Renal failure ; TRPC Cation Channels - genetics ; TRPC6 Cation Channel ; TRPC6 gene ; Young Adult</subject><ispartof>Nephrology, dialysis, transplantation, 2009-10, Vol.24 (10), p.3089-3096</ispartof><rights>Oxford University Press © The Author [2009]. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org 2009</rights><rights>2009 INIST-CNRS</rights><lds50>peer_reviewed</lds50><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c415t-f7452860a9d67aedd7989873d2a79383a426d5e7d5be60161e669cb954bdeeb3</citedby><cites>FETCH-LOGICAL-c415t-f7452860a9d67aedd7989873d2a79383a426d5e7d5be60161e669cb954bdeeb3</cites></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>315,786,790,1591,27957,27958</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=22013742$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/19458060$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>Santín, Sheila</creatorcontrib><creatorcontrib>Ars, Elisabet</creatorcontrib><creatorcontrib>Rossetti, Sandro</creatorcontrib><creatorcontrib>Salido, Eduardo</creatorcontrib><creatorcontrib>Silva, Irene</creatorcontrib><creatorcontrib>García-Maset, Rafael</creatorcontrib><creatorcontrib>Giménez, Isabel</creatorcontrib><creatorcontrib>Ruíz, Patricia</creatorcontrib><creatorcontrib>Mendizábal, Santiago</creatorcontrib><creatorcontrib>Luciano Nieto, José</creatorcontrib><creatorcontrib>Peña, Antonia</creatorcontrib><creatorcontrib>Camacho, Juan Antonio</creatorcontrib><creatorcontrib>Fraga, Gloria</creatorcontrib><creatorcontrib>Cobo, Mª Ángeles</creatorcontrib><creatorcontrib>Bernis, Carmen</creatorcontrib><creatorcontrib>Ortiz, Alberto</creatorcontrib><creatorcontrib>de Pablos, Augusto Luque</creatorcontrib><creatorcontrib>Sánchez-Moreno, Ana</creatorcontrib><creatorcontrib>Pintos, Guillem</creatorcontrib><creatorcontrib>Mirapeix, Eduard</creatorcontrib><creatorcontrib>Fernández-Llama, Patricia</creatorcontrib><creatorcontrib>Ballarín, José</creatorcontrib><creatorcontrib>Torra, Roser</creatorcontrib><creatorcontrib>FSGS Study Group</creatorcontrib><creatorcontrib>on behalf of the FSGS Study Group</creatorcontrib><title>TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis</title><title>Nephrology, dialysis, transplantation</title><addtitle>Nephrol Dial Transplant</addtitle><addtitle>Nephrol Dial Transplant</addtitle><description>Background. Mutations in the TRPC6 gene have been reported in six families with adult-onset (17–57 years) autosomal dominant focal segmental glomerulosclerosis (FSGS). Electrophysiology studies confirmed augmented calcium influx only in three of these six TRPC6 mutations. To date, the role of TRPC6 in childhood and adulthood non-familial forms is unknown. Methods. TRPC6 mutation analysis was performed by direct sequencing in 130 Spanish patients from 115 unrelated families with FSGS. An in silico scoring matrix was developed to evaluate the pathogenicity of amino acid substitutions, by using the bio-physical and bio-chemical differences between wild-type and mutant amino acid, the evolutionary conservation of the amino acid residue in orthologues, homologues and defined domains, with the addition of contextual information. Results. Three new missense substitutions were identified in two clinically non-familial cases and in one familial case. The analysis by means of this scoring system allowed us to classify these variants as likely pathogenic mutations. One of them was detected in a female patient with unusual clinical features: mesangial proliferative FSGS in childhood (7 years) and partial response to immunosupressive therapy (CsA + MMF). Asymptomatic carriers of this likely mutation were found within her family. Conclusions. We describe for the first time TRPC6 mutations in children and adults with non-familial FSGS. It seems that TRPC6 is a gene with a very variable penetrance that may contribute to glomerular diseases in a multi-hit setting.</description><subject>Adolescent</subject><subject>Adult</subject><subject>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</subject><subject>Biological and medical sciences</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>DNA Mutational Analysis</subject><subject>Emergency and intensive care: renal failure. Dialysis management</subject><subject>Female</subject><subject>focal segmental glomerulosclerosis</subject><subject>Glomerulonephritis</subject><subject>Glomerulosclerosis, Focal Segmental - genetics</subject><subject>Humans</subject><subject>in silico scoring system</subject><subject>Infant</subject><subject>Intensive care medicine</subject><subject>Medical sciences</subject><subject>Middle Aged</subject><subject>missense substitutions</subject><subject>mutation analysis</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Nephropathies. Renovascular diseases. Renal failure</subject><subject>TRPC Cation Channels - genetics</subject><subject>TRPC6 Cation Channel</subject><subject>TRPC6 gene</subject><subject>Young Adult</subject><issn>0931-0509</issn><issn>1460-2385</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2009</creationdate><recordtype>article</recordtype><recordid>eNp90E9rFDEYBvAgit1WL34AyUUFYWz-Z3KUwbbCokUXFC8hM3lnOzozGZMM2m9vZJf21ksSkl-ekAehF5S8o8Tw89nn832_MGYeoQ0VilSM1_Ix2pRDWhFJzAk6TeknIcQwrZ-iE2qErIkiG2R3X64bhac1uzyE2Y3YleE2DQkPM3Z4dHEPuAs3IWYcerwUBnNO-M-Qb3AfunIjwX4qe2W1H8MEcR1D6kaIoaQ8Q096NyZ4fpzP0O7iw665qrafLz8277dVJ6jMVa-FZLUiznilHXivTW1qzT1z2vCaO8GUl6C9bEERqigoZbrWSNF6gJafoTeH2CWG3yukbKchdTCOboawJqu5IFLUghb5-kHJKKXGGF3g2wPsykdShN4ucZhcvLWU2P-929K7PfRe8Mtj6tpO4O_psegCXh2BS6WzPrq5G9KdY4xQrgW7d2FdHn6wOrghZfh7J138ZZXmWtqr7z9sc_3t4mtTf7Jb_g97oahr</recordid><startdate>20091001</startdate><enddate>20091001</enddate><creator>Santín, Sheila</creator><creator>Ars, Elisabet</creator><creator>Rossetti, Sandro</creator><creator>Salido, Eduardo</creator><creator>Silva, Irene</creator><creator>García-Maset, Rafael</creator><creator>Giménez, Isabel</creator><creator>Ruíz, Patricia</creator><creator>Mendizábal, Santiago</creator><creator>Luciano Nieto, José</creator><creator>Peña, Antonia</creator><creator>Camacho, Juan Antonio</creator><creator>Fraga, Gloria</creator><creator>Cobo, Mª Ángeles</creator><creator>Bernis, Carmen</creator><creator>Ortiz, Alberto</creator><creator>de Pablos, Augusto Luque</creator><creator>Sánchez-Moreno, Ana</creator><creator>Pintos, Guillem</creator><creator>Mirapeix, Eduard</creator><creator>Fernández-Llama, Patricia</creator><creator>Ballarín, José</creator><creator>Torra, Roser</creator><general>Oxford University Press</general><scope>BSCLL</scope><scope>IQODW</scope><scope>CGR</scope><scope>CUY</scope><scope>CVF</scope><scope>ECM</scope><scope>EIF</scope><scope>NPM</scope><scope>AAYXX</scope><scope>CITATION</scope><scope>7QP</scope><scope>7X8</scope></search><sort><creationdate>20091001</creationdate><title>TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis</title><author>Santín, Sheila ; Ars, Elisabet ; Rossetti, Sandro ; Salido, Eduardo ; Silva, Irene ; García-Maset, Rafael ; Giménez, Isabel ; Ruíz, Patricia ; Mendizábal, Santiago ; Luciano Nieto, José ; Peña, Antonia ; Camacho, Juan Antonio ; Fraga, Gloria ; Cobo, Mª Ángeles ; Bernis, Carmen ; Ortiz, Alberto ; de Pablos, Augusto Luque ; Sánchez-Moreno, Ana ; Pintos, Guillem ; Mirapeix, Eduard ; Fernández-Llama, Patricia ; Ballarín, José ; Torra, Roser</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c415t-f7452860a9d67aedd7989873d2a79383a426d5e7d5be60161e669cb954bdeeb3</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2009</creationdate><topic>Adolescent</topic><topic>Adult</topic><topic>Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy</topic><topic>Biological and medical sciences</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>DNA Mutational Analysis</topic><topic>Emergency and intensive care: renal failure. Dialysis management</topic><topic>Female</topic><topic>focal segmental glomerulosclerosis</topic><topic>Glomerulonephritis</topic><topic>Glomerulosclerosis, Focal Segmental - genetics</topic><topic>Humans</topic><topic>in silico scoring system</topic><topic>Infant</topic><topic>Intensive care medicine</topic><topic>Medical sciences</topic><topic>Middle Aged</topic><topic>missense substitutions</topic><topic>mutation analysis</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Nephropathies. Renovascular diseases. Renal failure</topic><topic>TRPC Cation Channels - genetics</topic><topic>TRPC6 Cation Channel</topic><topic>TRPC6 gene</topic><topic>Young Adult</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>Santín, Sheila</creatorcontrib><creatorcontrib>Ars, Elisabet</creatorcontrib><creatorcontrib>Rossetti, Sandro</creatorcontrib><creatorcontrib>Salido, Eduardo</creatorcontrib><creatorcontrib>Silva, Irene</creatorcontrib><creatorcontrib>García-Maset, Rafael</creatorcontrib><creatorcontrib>Giménez, Isabel</creatorcontrib><creatorcontrib>Ruíz, Patricia</creatorcontrib><creatorcontrib>Mendizábal, Santiago</creatorcontrib><creatorcontrib>Luciano Nieto, José</creatorcontrib><creatorcontrib>Peña, Antonia</creatorcontrib><creatorcontrib>Camacho, Juan Antonio</creatorcontrib><creatorcontrib>Fraga, Gloria</creatorcontrib><creatorcontrib>Cobo, Mª Ángeles</creatorcontrib><creatorcontrib>Bernis, Carmen</creatorcontrib><creatorcontrib>Ortiz, Alberto</creatorcontrib><creatorcontrib>de Pablos, Augusto Luque</creatorcontrib><creatorcontrib>Sánchez-Moreno, Ana</creatorcontrib><creatorcontrib>Pintos, Guillem</creatorcontrib><creatorcontrib>Mirapeix, Eduard</creatorcontrib><creatorcontrib>Fernández-Llama, Patricia</creatorcontrib><creatorcontrib>Ballarín, José</creatorcontrib><creatorcontrib>Torra, Roser</creatorcontrib><creatorcontrib>FSGS Study Group</creatorcontrib><creatorcontrib>on behalf of the FSGS Study Group</creatorcontrib><collection>Istex</collection><collection>Pascal-Francis</collection><collection>Medline</collection><collection>MEDLINE</collection><collection>MEDLINE (Ovid)</collection><collection>MEDLINE</collection><collection>MEDLINE</collection><collection>PubMed</collection><collection>CrossRef</collection><collection>Calcium & Calcified Tissue Abstracts</collection><collection>MEDLINE - Academic</collection><jtitle>Nephrology, dialysis, transplantation</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>Santín, Sheila</au><au>Ars, Elisabet</au><au>Rossetti, Sandro</au><au>Salido, Eduardo</au><au>Silva, Irene</au><au>García-Maset, Rafael</au><au>Giménez, Isabel</au><au>Ruíz, Patricia</au><au>Mendizábal, Santiago</au><au>Luciano Nieto, José</au><au>Peña, Antonia</au><au>Camacho, Juan Antonio</au><au>Fraga, Gloria</au><au>Cobo, Mª Ángeles</au><au>Bernis, Carmen</au><au>Ortiz, Alberto</au><au>de Pablos, Augusto Luque</au><au>Sánchez-Moreno, Ana</au><au>Pintos, Guillem</au><au>Mirapeix, Eduard</au><au>Fernández-Llama, Patricia</au><au>Ballarín, José</au><au>Torra, Roser</au><aucorp>FSGS Study Group</aucorp><aucorp>on behalf of the FSGS Study Group</aucorp><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis</atitle><jtitle>Nephrology, dialysis, transplantation</jtitle><stitle>Nephrol Dial Transplant</stitle><addtitle>Nephrol Dial Transplant</addtitle><date>2009-10-01</date><risdate>2009</risdate><volume>24</volume><issue>10</issue><spage>3089</spage><epage>3096</epage><pages>3089-3096</pages><issn>0931-0509</issn><eissn>1460-2385</eissn><coden>NDTREA</coden><notes>ark:/67375/HXZ-CPWFSC8N-L</notes><notes>Other investigators in the FSGS Study Group are listed below: Hospital Universitario La Fe- Isabel Zamora; Hospital Vall d’Hebron- Joan López-Hellin, Álvaro Madrid, Clara Ventura, Ramón Vilalta; Hospital Infantil La Paz- Laura Espinosa, Carmen García, Marta Melgosa, Mercedes Navarro; Hospital Sant Joan de Déu- Antonio Giménez, Jorge Vila Cots; Fundación Jiménez Díaz- Simona Alexandra, Carlos Caramelo†, Jesús Egido; Hospital General Universitario Gregorio Marañón- M Dolores Morales San José; Hospital Infantil Universitario Virgen del Rocío- Francisco de la Cerda; Hospital de Barcelona- Pere Sala, Frederic Raspall, Ángel Vila; Hospital Torrecárdenas- Antonio María Daza; Hospital Niño Jesús- Mercedes Vázquez, José Luis Écija; Hospital Universitario Reina Sofía- Mario Espinosa; Hospital Infantil Miguel Servet- Ma Luisa Justa; Hospital Princeps d’España- Rafael Poveda; Hospital Universitario de Getafe- Cristina Aparicio; Hospital Materno-Infantil Son Dureta- Jordi Rosell; Hospital Infantil doce de Octubre- Rafael Muley; Hospital de Galdakao- Jesús Montenegro; Hospital Universitario Marqués de Valdecilla- Domingo González; Hospital Materno-Infantil de Badajoz- Emilia Hidalgo; Hospital Universitario Virgen de las Nieves- David Barajas de Frutos; Hospital Son Llàtzer- Esther Trillo; Hospital Universitario Virgen de la Arrixaca- Salvador Gracia; Hospital de Cruces- Francisco Javier Gainza de los Ríos.</notes><notes>ArticleID:gfp229</notes><notes>istex:6F1F90EB7CE79F5599E83A4D9F63001BAD51FD6A</notes><notes>ObjectType-Article-2</notes><notes>SourceType-Scholarly Journals-1</notes><notes>ObjectType-Feature-1</notes><notes>content type line 23</notes><notes>ObjectType-Case Study-2</notes><notes>ObjectType-Feature-4</notes><notes>ObjectType-Report-1</notes><notes>ObjectType-Article-3</notes><abstract>Background. Mutations in the TRPC6 gene have been reported in six families with adult-onset (17–57 years) autosomal dominant focal segmental glomerulosclerosis (FSGS). Electrophysiology studies confirmed augmented calcium influx only in three of these six TRPC6 mutations. To date, the role of TRPC6 in childhood and adulthood non-familial forms is unknown. Methods. TRPC6 mutation analysis was performed by direct sequencing in 130 Spanish patients from 115 unrelated families with FSGS. An in silico scoring matrix was developed to evaluate the pathogenicity of amino acid substitutions, by using the bio-physical and bio-chemical differences between wild-type and mutant amino acid, the evolutionary conservation of the amino acid residue in orthologues, homologues and defined domains, with the addition of contextual information. Results. Three new missense substitutions were identified in two clinically non-familial cases and in one familial case. The analysis by means of this scoring system allowed us to classify these variants as likely pathogenic mutations. One of them was detected in a female patient with unusual clinical features: mesangial proliferative FSGS in childhood (7 years) and partial response to immunosupressive therapy (CsA + MMF). Asymptomatic carriers of this likely mutation were found within her family. Conclusions. We describe for the first time TRPC6 mutations in children and adults with non-familial FSGS. It seems that TRPC6 is a gene with a very variable penetrance that may contribute to glomerular diseases in a multi-hit setting.</abstract><cop>Oxford</cop><pub>Oxford University Press</pub><pmid>19458060</pmid><doi>10.1093/ndt/gfp229</doi><tpages>8</tpages></addata></record> |
| fulltext | fulltext |
| identifier | ISSN: 0931-0509 |
| ispartof | Nephrology, dialysis, transplantation, 2009-10, Vol.24 (10), p.3089-3096 |
| issn | 0931-0509 1460-2385 |
| language | eng |
| recordid | cdi_proquest_miscellaneous_734054841 |
| source | Oxford University Press |
| subjects | Adolescent Adult Anesthesia. Intensive care medicine. Transfusions. Cell therapy and gene therapy Biological and medical sciences Child Child, Preschool DNA Mutational Analysis Emergency and intensive care: renal failure. Dialysis management Female focal segmental glomerulosclerosis Glomerulonephritis Glomerulosclerosis, Focal Segmental - genetics Humans in silico scoring system Infant Intensive care medicine Medical sciences Middle Aged missense substitutions mutation analysis Nephrology. Urinary tract diseases Nephropathies. Renovascular diseases. Renal failure TRPC Cation Channels - genetics TRPC6 Cation Channel TRPC6 gene Young Adult |
| title | TRPC6 mutational analysis in a large cohort of patients with focal segmental glomerulosclerosis |
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