{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,2,17]],"date-time":"2026-02-17T04:49:52Z","timestamp":1771303792560,"version":"3.50.1"},"reference-count":27,"publisher":"BMJ","issue":"2","content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["J Med Genet"],"published-print":{"date-parts":[[2003,2]]},"abstract":"<jats:p>The rare bone thickening disease osteopetrosis occurs in various forms, one of which is accompanied by renal tubular acidosis (RTA), and is known as Guibaud-Vainsel syndrome or marble brain disease. Clinical manifestations of this autosomal recessive syndrome comprise increased bone density, growth failure, intracerebral calcification, facial dysmorphism, mental retardation, and conductive hearing impairment. The most common cause is carbonic anhydrase II (CAII) deficiency. Several different loss of function mutations in <jats:italic>CA2<\/jats:italic>, the gene encoding CAII, have been described. To date, there have been no exceptions to the finding of CAII deficiency in patients with coexistent osteopetrosis and RTA. Most often, the RTA is of mixed proximal and distal type, but kindreds are reported in which either distal or proximal RTA predominates.<\/jats:p>\n               <jats:p>We report the molecular genetic investigation of two consanguineous kindreds where osteopetrosis and distal RTA (dRTA) were both manifest. One kindred harbours a novel homozygous frameshift alteration in <jats:italic>CA2<\/jats:italic>. In the other, CAII levels were normal despite a similar clinical picture, and we excluded defects in <jats:italic>CA2<\/jats:italic>. In this kindred, two separate recessive disorders are penetrant, each affecting a different, tissue specific subunit of the vacuolar proton pump (H<jats:sup>+<\/jats:sup>-ATPase), providing a highly unusual, novel genetic explanation for the coexistence of osteopetrosis and dRTA. The osteopetrosis is the result of a homozygous deletion in <jats:italic>TCIRG1,<\/jats:italic> which encodes an osteoclast specific isoform of subunit a of the H<jats:sup>+<\/jats:sup>-ATPase, while the dRTA is associated with a homozygous mutation in <jats:italic>ATP6V1B1,<\/jats:italic> encoding the kidney specific B1 subunit of H<jats:sup>+<\/jats:sup>-ATPase.<\/jats:p>\n               <jats:p>This kindred is exceptional firstly because the coinheritance of two rare recessive disorders has created a phenocopy of CAII deficiency, and secondly because these disorders affect two different subunits of the H<jats:sup>+<\/jats:sup>-ATPase that have opposite effects on bone density, but which have only recently been determined to possess tissue specific isoforms.<\/jats:p>","DOI":"10.1136\/jmg.40.2.115","type":"journal-article","created":{"date-parts":[[2003,2,3]],"date-time":"2003-02-03T18:44:14Z","timestamp":1044297854000},"page":"115-121","source":"Crossref","is-referenced-by-count":88,"title":["A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis"],"prefix":"10.1136","volume":"40","author":[{"given":"K J","family":"Borthwick","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N","family":"Kandemir","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"R","family":"Topaloglu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"U","family":"Kornak","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"A","family":"Bakkaloglu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"N","family":"Yordam","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"S","family":"Ozen","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"H","family":"Mocan","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"G N","family":"Shah","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"W S","family":"Sly","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"F E","family":"Karet","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"239","published-online":{"date-parts":[[2003,2,1]]},"reference":[{"key":"2025101721505017000_40.2.115.1","first-page":"269","volume":"29","year":"1972","journal-title":"Arch Fr Pediatr"},{"key":"2025101721505017000_40.2.115.2","doi-asserted-by":"crossref","first-page":"429","DOI":"10.1111\/j.1651-2227.1972.tb15859.x","volume":"61","year":"1972","journal-title":"Acta Paediatr Scand"},{"key":"2025101721505017000_40.2.115.3","first-page":"34A","volume":"24","year":"1972","journal-title":"Am J Hum Genet"},{"key":"2025101721505017000_40.2.115.4","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.80.9.2752"},{"key":"2025101721505017000_40.2.115.5","doi-asserted-by":"crossref","first-page":"886","DOI":"10.1038\/ki.1984.106","volume":"25","year":"1984","journal-title":"Kidney Int"},{"key":"2025101721505017000_40.2.115.6","doi-asserted-by":"publisher","DOI":"10.1016\/0002-9343(80)90501-X"},{"key":"2025101721505017000_40.2.115.7","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(98)70367-1"},{"key":"2025101721505017000_40.2.115.8","doi-asserted-by":"crossref","first-page":"594","DOI":"10.1056\/NEJM198803103181002","volume":"318","year":"1988","journal-title":"N Engl J Med"},{"key":"2025101721505017000_40.2.115.9","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.78.9.5759"},{"key":"2025101721505017000_40.2.115.10","doi-asserted-by":"publisher","DOI":"10.1016\/0092-8674(94)90250-X"},{"key":"2025101721505017000_40.2.115.11","doi-asserted-by":"publisher","DOI":"10.1038\/5022"},{"key":"2025101721505017000_40.2.115.12","doi-asserted-by":"crossref","first-page":"26","DOI":"10.1016\/S0022-3565(25)25860-8","volume":"130","year":"1960","journal-title":"J Pharmacol Exp Ther"},{"key":"2025101721505017000_40.2.115.13","first-page":"125","volume":"38","year":"1986","journal-title":"Am J Hum Genet"},{"key":"2025101721505017000_40.2.115.14","doi-asserted-by":"publisher","DOI":"10.1038\/77131"},{"key":"2025101721505017000_40.2.115.15","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.13.2059"},{"key":"2025101721505017000_40.2.115.16","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(80)80012-6"},{"key":"2025101721505017000_40.2.115.17","doi-asserted-by":"publisher","DOI":"10.1007\/BF00367382"},{"key":"2025101721505017000_40.2.115.18","doi-asserted-by":"publisher","DOI":"10.1002\/(SICI)1098-1004(1997)9:5<383::AID-HUMU1>3.0.CO;2-5"},{"key":"2025101721505017000_40.2.115.19","unstructured":"Sly W, Shah G. Osteopetrosis with renal tubular acidosis and cerebral calcification. In: Scriver C, ed. The metabolic and molecular bases of inherited disease. 8th ed. New York: McGraw-Hill, 2001:5331-43."},{"key":"2025101721505017000_40.2.115.20","doi-asserted-by":"publisher","DOI":"10.1007\/s004390050419"},{"key":"2025101721505017000_40.2.115.21","first-page":"1671","volume":"14","year":"2001","journal-title":"J Pediatr Endocrinol Metab"},{"key":"2025101721505017000_40.2.115.22","doi-asserted-by":"crossref","first-page":"1","DOI":"10.1016\/S0002-9394(14)76929-6","volume":"110","year":"1990","journal-title":"Am J Ophthalmol"},{"key":"2025101721505017000_40.2.115.23","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V97.7.1947"},{"key":"2025101721505017000_40.2.115.24","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.4.2018"},{"key":"2025101721505017000_40.2.115.25","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.271.37.22487"},{"key":"2025101721505017000_40.2.115.26","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.273.12.6717"},{"key":"2025101721505017000_40.2.115.27","doi-asserted-by":"publisher","DOI":"10.1006\/geno.1999.5751"}],"container-title":["Journal of Medical Genetics"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.1136\/jmg.40.2.115","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,10,18]],"date-time":"2025-10-18T04:50:59Z","timestamp":1760763059000},"score":1,"resource":{"primary":{"URL":"https:\/\/jmg.bmj.com\/lookup\/doi\/10.1136\/jmg.40.2.115"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2003,2]]},"references-count":27,"journal-issue":{"issue":"2","published-online":{"date-parts":[[2003,2,1]]},"published-print":{"date-parts":[[2003,2]]}},"alternative-id":["10.1136\/jmg.40.2.115"],"URL":"https:\/\/doi.org\/10.1136\/jmg.40.2.115","relation":{},"ISSN":["0022-2593","1468-6244"],"issn-type":[{"value":"0022-2593","type":"print"},{"value":"1468-6244","type":"electronic"}],"subject":[],"published":{"date-parts":[[2003,2]]}}}