Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis
Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disorder that is frequently associated with progressive renal failure. The primary defect is related to impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of Hen...
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| Veröffentlicht in: | Journal of the American Society of Nephrology 2001-09, Vol.12 (9), p.1872-1881 |
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| creator | WEBER, Stefanie SCHNEIDER, Linda GREGORIC, Alojz PALCOUX, Jean-Bernard TASIC, Velibor MANZ, Friedrich SCHÄRER, Karl SEYBERTH, Hannsjörg W KONRAD, Martin PETERS, Melanie MISSELWITZ, Joachim RÖNNEFARTH, Gabriele BÖSWALD, Michael BONZEL, Klaus E SEEMAN, Tomas SULAKOVA, Tereza KUWERTZ-BRÖKING, Eberhard |
| description | Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disorder that is frequently associated with progressive renal failure. The primary defect is related to impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop. Mutations in PCLN-1, which encodes the renal tight junction protein paracellin-1 (claudin-16), were identified as the underlying genetic defects. Comprehensive clinical data and the results of PCLN-1 mutation analysis of 25 FHHNC families with 33 affected individuals are presented. Patients presented mainly with urinary tract infections, polyuria, and hematuria at a median age of 3.5 yr. At the time of diagnosis, the GFR was already decreased to |
| doi_str_mv | 10.1681/ASN.V1291872 |
| format | Article |
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The primary defect is related to impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop. Mutations in PCLN-1, which encodes the renal tight junction protein paracellin-1 (claudin-16), were identified as the underlying genetic defects. Comprehensive clinical data and the results of PCLN-1 mutation analysis of 25 FHHNC families with 33 affected individuals are presented. Patients presented mainly with urinary tract infections, polyuria, and hematuria at a median age of 3.5 yr. At the time of diagnosis, the GFR was already decreased to <60 ml/min per 1.73 m(2) for 11 patients. Twelve patients exhibited progression to end-stage renal disease, at a median age of 14.5 yr. Treatment with magnesium salts and thiazides seemed to have no effect on the progression of the disease. Genotype analysis revealed PCLN-1 mutations in all except three mutant alleles (94%). Fifteen different mutations were observed, including eight novel mutations. The accumulation of mutations affecting the first extracellular loop was striking, with 48% of all mutant alleles exhibiting a Leu151Phe exchange. Haplotype analysis strongly suggested a founder effect among patients with FHHNC who originated from Germany or eastern European countries. In 13 of 23 families, hypercalciuria and/or nephrolithiasis were observed in otherwise unaffected family members, indicating a possible role of heterozygous PCLN-1 mutations in yielding hypercalciuric stone-forming conditions.</description><identifier>ISSN: 1046-6673</identifier><identifier>EISSN: 1533-3450</identifier><identifier>DOI: 10.1681/ASN.V1291872</identifier><identifier>PMID: 11518780</identifier><identifier>CODEN: JASNEU</identifier><language>eng</language><publisher>Hagerstown, MD: Lippincott Williams & Wilkins</publisher><subject>Adolescent ; Amino Acid Sequence - genetics ; Biological and medical sciences ; Calcium - urine ; Child ; Child, Preschool ; Claudins ; Cohort Studies ; Female ; Genotype ; Humans ; Infant ; Kidney - physiopathology ; Magnesium - blood ; Male ; Medical sciences ; Membrane Proteins - genetics ; Molecular Sequence Data ; Mutation - genetics ; Nephrocalcinosis - genetics ; Nephrocalcinosis - metabolism ; Nephrocalcinosis - physiopathology ; Nephrology. Urinary tract diseases ; Pedigree ; Phenotype ; Urinary lithiasis</subject><ispartof>Journal of the American Society of Nephrology, 2001-09, Vol.12 (9), p.1872-1881</ispartof><rights>2001 INIST-CNRS</rights><lds50>peer_reviewed</lds50><oa>free_for_read</oa><woscitedreferencessubscribed>false</woscitedreferencessubscribed><citedby>FETCH-LOGICAL-c354t-31264fd77ffbc770bbbc6b4f1681d86ae4b90d13bea4bf88936d75338f7a2dd83</citedby></display><links><openurl>$$Topenurl_article</openurl><openurlfulltext>$$Topenurlfull_article</openurlfulltext><thumbnail>$$Tsyndetics_thumb_exl</thumbnail><link.rule.ids>314,776,780,27901,27902</link.rule.ids><backlink>$$Uhttp://pascal-francis.inist.fr/vibad/index.php?action=getRecordDetail&idt=1118769$$DView record in Pascal Francis$$Hfree_for_read</backlink><backlink>$$Uhttps://www.ncbi.nlm.nih.gov/pubmed/11518780$$D View this record in MEDLINE/PubMed$$Hfree_for_read</backlink></links><search><creatorcontrib>WEBER, Stefanie</creatorcontrib><creatorcontrib>SCHNEIDER, Linda</creatorcontrib><creatorcontrib>GREGORIC, Alojz</creatorcontrib><creatorcontrib>PALCOUX, Jean-Bernard</creatorcontrib><creatorcontrib>TASIC, Velibor</creatorcontrib><creatorcontrib>MANZ, Friedrich</creatorcontrib><creatorcontrib>SCHÄRER, Karl</creatorcontrib><creatorcontrib>SEYBERTH, Hannsjörg W</creatorcontrib><creatorcontrib>KONRAD, Martin</creatorcontrib><creatorcontrib>PETERS, Melanie</creatorcontrib><creatorcontrib>MISSELWITZ, Joachim</creatorcontrib><creatorcontrib>RÖNNEFARTH, Gabriele</creatorcontrib><creatorcontrib>BÖSWALD, Michael</creatorcontrib><creatorcontrib>BONZEL, Klaus E</creatorcontrib><creatorcontrib>SEEMAN, Tomas</creatorcontrib><creatorcontrib>SULAKOVA, Tereza</creatorcontrib><creatorcontrib>KUWERTZ-BRÖKING, Eberhard</creatorcontrib><title>Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis</title><title>Journal of the American Society of Nephrology</title><addtitle>J Am Soc Nephrol</addtitle><description>Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disorder that is frequently associated with progressive renal failure. The primary defect is related to impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop. Mutations in PCLN-1, which encodes the renal tight junction protein paracellin-1 (claudin-16), were identified as the underlying genetic defects. Comprehensive clinical data and the results of PCLN-1 mutation analysis of 25 FHHNC families with 33 affected individuals are presented. Patients presented mainly with urinary tract infections, polyuria, and hematuria at a median age of 3.5 yr. At the time of diagnosis, the GFR was already decreased to <60 ml/min per 1.73 m(2) for 11 patients. Twelve patients exhibited progression to end-stage renal disease, at a median age of 14.5 yr. Treatment with magnesium salts and thiazides seemed to have no effect on the progression of the disease. Genotype analysis revealed PCLN-1 mutations in all except three mutant alleles (94%). Fifteen different mutations were observed, including eight novel mutations. The accumulation of mutations affecting the first extracellular loop was striking, with 48% of all mutant alleles exhibiting a Leu151Phe exchange. Haplotype analysis strongly suggested a founder effect among patients with FHHNC who originated from Germany or eastern European countries. In 13 of 23 families, hypercalciuria and/or nephrolithiasis were observed in otherwise unaffected family members, indicating a possible role of heterozygous PCLN-1 mutations in yielding hypercalciuric stone-forming conditions.</description><subject>Adolescent</subject><subject>Amino Acid Sequence - genetics</subject><subject>Biological and medical sciences</subject><subject>Calcium - urine</subject><subject>Child</subject><subject>Child, Preschool</subject><subject>Claudins</subject><subject>Cohort Studies</subject><subject>Female</subject><subject>Genotype</subject><subject>Humans</subject><subject>Infant</subject><subject>Kidney - physiopathology</subject><subject>Magnesium - blood</subject><subject>Male</subject><subject>Medical sciences</subject><subject>Membrane Proteins - genetics</subject><subject>Molecular Sequence Data</subject><subject>Mutation - genetics</subject><subject>Nephrocalcinosis - genetics</subject><subject>Nephrocalcinosis - metabolism</subject><subject>Nephrocalcinosis - physiopathology</subject><subject>Nephrology. Urinary tract diseases</subject><subject>Pedigree</subject><subject>Phenotype</subject><subject>Urinary lithiasis</subject><issn>1046-6673</issn><issn>1533-3450</issn><fulltext>true</fulltext><rsrctype>article</rsrctype><creationdate>2001</creationdate><recordtype>article</recordtype><sourceid>EIF</sourceid><recordid>eNpNkL1PwzAQxS0EoqWwMaMMiIkUO07sdKwqvqSqDHys0dmxqVHipHYC6n-PS4Ngurt3P93pPYTOCZ4SlpOb-fNq-kaSGcl5coDGJKM0pmmGD0OPUxYzxukInXj_gTHJEs6P0YiQLOA5HqPNqvlUVdSCA6mqytiYRHXfQWca6yNjoySLNNSmMspHX6ZbDxNU0XrbNjW8W-VVbWC_DJpyEippehc0sGVkVbt2zY9mG2_8KTrSUHl1NtQJer27fVk8xMun-8fFfBlLmqVdTEnCUl1yrrWQnGMhhGQi1TvPZc5ApWKGS0KFglToPJ9RVvLgPdcckrLM6QRd7e-2rtn0yndFbfzOI1jV9L7ghBAWAgrg9R6UrvHeKV20ztTgtgXBxe5dESIufiMO-MVwtxe1Kv_gIdMAXA4A-GBbO7DS-H9cwNiMfgOOl4XU</recordid><startdate>20010901</startdate><enddate>20010901</enddate><creator>WEBER, Stefanie</creator><creator>SCHNEIDER, Linda</creator><creator>GREGORIC, Alojz</creator><creator>PALCOUX, Jean-Bernard</creator><creator>TASIC, Velibor</creator><creator>MANZ, Friedrich</creator><creator>SCHÄRER, Karl</creator><creator>SEYBERTH, Hannsjörg W</creator><creator>KONRAD, Martin</creator><creator>PETERS, Melanie</creator><creator>MISSELWITZ, Joachim</creator><creator>RÖNNEFARTH, Gabriele</creator><creator>BÖSWALD, Michael</creator><creator>BONZEL, Klaus E</creator><creator>SEEMAN, Tomas</creator><creator>SULAKOVA, Tereza</creator><creator>KUWERTZ-BRÖKING, Eberhard</creator><general>Lippincott Williams & Wilkins</general><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>7X8</scope></search><sort><creationdate>20010901</creationdate><title>Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis</title><author>WEBER, Stefanie ; SCHNEIDER, Linda ; GREGORIC, Alojz ; PALCOUX, Jean-Bernard ; TASIC, Velibor ; MANZ, Friedrich ; SCHÄRER, Karl ; SEYBERTH, Hannsjörg W ; KONRAD, Martin ; PETERS, Melanie ; MISSELWITZ, Joachim ; RÖNNEFARTH, Gabriele ; BÖSWALD, Michael ; BONZEL, Klaus E ; SEEMAN, Tomas ; SULAKOVA, Tereza ; KUWERTZ-BRÖKING, Eberhard</author></sort><facets><frbrtype>5</frbrtype><frbrgroupid>cdi_FETCH-LOGICAL-c354t-31264fd77ffbc770bbbc6b4f1681d86ae4b90d13bea4bf88936d75338f7a2dd83</frbrgroupid><rsrctype>articles</rsrctype><prefilter>articles</prefilter><language>eng</language><creationdate>2001</creationdate><topic>Adolescent</topic><topic>Amino Acid Sequence - genetics</topic><topic>Biological and medical sciences</topic><topic>Calcium - urine</topic><topic>Child</topic><topic>Child, Preschool</topic><topic>Claudins</topic><topic>Cohort Studies</topic><topic>Female</topic><topic>Genotype</topic><topic>Humans</topic><topic>Infant</topic><topic>Kidney - physiopathology</topic><topic>Magnesium - blood</topic><topic>Male</topic><topic>Medical sciences</topic><topic>Membrane Proteins - genetics</topic><topic>Molecular Sequence Data</topic><topic>Mutation - genetics</topic><topic>Nephrocalcinosis - genetics</topic><topic>Nephrocalcinosis - metabolism</topic><topic>Nephrocalcinosis - physiopathology</topic><topic>Nephrology. Urinary tract diseases</topic><topic>Pedigree</topic><topic>Phenotype</topic><topic>Urinary lithiasis</topic><toplevel>peer_reviewed</toplevel><toplevel>online_resources</toplevel><creatorcontrib>WEBER, Stefanie</creatorcontrib><creatorcontrib>SCHNEIDER, Linda</creatorcontrib><creatorcontrib>GREGORIC, Alojz</creatorcontrib><creatorcontrib>PALCOUX, Jean-Bernard</creatorcontrib><creatorcontrib>TASIC, Velibor</creatorcontrib><creatorcontrib>MANZ, Friedrich</creatorcontrib><creatorcontrib>SCHÄRER, Karl</creatorcontrib><creatorcontrib>SEYBERTH, Hannsjörg W</creatorcontrib><creatorcontrib>KONRAD, Martin</creatorcontrib><creatorcontrib>PETERS, Melanie</creatorcontrib><creatorcontrib>MISSELWITZ, Joachim</creatorcontrib><creatorcontrib>RÖNNEFARTH, Gabriele</creatorcontrib><creatorcontrib>BÖSWALD, Michael</creatorcontrib><creatorcontrib>BONZEL, Klaus E</creatorcontrib><creatorcontrib>SEEMAN, Tomas</creatorcontrib><creatorcontrib>SULAKOVA, Tereza</creatorcontrib><creatorcontrib>KUWERTZ-BRÖKING, Eberhard</creatorcontrib><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>MEDLINE - Academic</collection><jtitle>Journal of the American Society of Nephrology</jtitle></facets><delivery><delcategory>Remote Search Resource</delcategory><fulltext>fulltext</fulltext></delivery><addata><au>WEBER, Stefanie</au><au>SCHNEIDER, Linda</au><au>GREGORIC, Alojz</au><au>PALCOUX, Jean-Bernard</au><au>TASIC, Velibor</au><au>MANZ, Friedrich</au><au>SCHÄRER, Karl</au><au>SEYBERTH, Hannsjörg W</au><au>KONRAD, Martin</au><au>PETERS, Melanie</au><au>MISSELWITZ, Joachim</au><au>RÖNNEFARTH, Gabriele</au><au>BÖSWALD, Michael</au><au>BONZEL, Klaus E</au><au>SEEMAN, Tomas</au><au>SULAKOVA, Tereza</au><au>KUWERTZ-BRÖKING, Eberhard</au><format>journal</format><genre>article</genre><ristype>JOUR</ristype><atitle>Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis</atitle><jtitle>Journal of the American Society of Nephrology</jtitle><addtitle>J Am Soc Nephrol</addtitle><date>2001-09-01</date><risdate>2001</risdate><volume>12</volume><issue>9</issue><spage>1872</spage><epage>1881</epage><pages>1872-1881</pages><issn>1046-6673</issn><eissn>1533-3450</eissn><coden>JASNEU</coden><abstract>Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive tubular disorder that is frequently associated with progressive renal failure. The primary defect is related to impaired tubular reabsorption of magnesium and calcium in the thick ascending limb of Henle's loop. Mutations in PCLN-1, which encodes the renal tight junction protein paracellin-1 (claudin-16), were identified as the underlying genetic defects. Comprehensive clinical data and the results of PCLN-1 mutation analysis of 25 FHHNC families with 33 affected individuals are presented. Patients presented mainly with urinary tract infections, polyuria, and hematuria at a median age of 3.5 yr. At the time of diagnosis, the GFR was already decreased to <60 ml/min per 1.73 m(2) for 11 patients. Twelve patients exhibited progression to end-stage renal disease, at a median age of 14.5 yr. Treatment with magnesium salts and thiazides seemed to have no effect on the progression of the disease. Genotype analysis revealed PCLN-1 mutations in all except three mutant alleles (94%). Fifteen different mutations were observed, including eight novel mutations. The accumulation of mutations affecting the first extracellular loop was striking, with 48% of all mutant alleles exhibiting a Leu151Phe exchange. Haplotype analysis strongly suggested a founder effect among patients with FHHNC who originated from Germany or eastern European countries. In 13 of 23 families, hypercalciuria and/or nephrolithiasis were observed in otherwise unaffected family members, indicating a possible role of heterozygous PCLN-1 mutations in yielding hypercalciuric stone-forming conditions.</abstract><cop>Hagerstown, MD</cop><pub>Lippincott Williams & Wilkins</pub><pmid>11518780</pmid><doi>10.1681/ASN.V1291872</doi><tpages>10</tpages><oa>free_for_read</oa></addata></record> |
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| subjects | Adolescent Amino Acid Sequence - genetics Biological and medical sciences Calcium - urine Child Child, Preschool Claudins Cohort Studies Female Genotype Humans Infant Kidney - physiopathology Magnesium - blood Male Medical sciences Membrane Proteins - genetics Molecular Sequence Data Mutation - genetics Nephrocalcinosis - genetics Nephrocalcinosis - metabolism Nephrocalcinosis - physiopathology Nephrology. Urinary tract diseases Pedigree Phenotype Urinary lithiasis |
| title | Novel paracellin-1 mutations in 25 families with familial hypomagnesemia with hypercalciuria and nephrocalcinosis |
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