PMID- 12566520
OWN - NLM
STAT- MEDLINE
DCOM- 20030310
LR  - 20190503
IS  - 1468-6244 (Electronic)
IS  - 0022-2593 (Print)
IS  - 0022-2593 (Linking)
VI  - 40
IP  - 2
DP  - 2003 Feb
TI  - A phenocopy of CAII deficiency: a novel genetic explanation for inherited 
      infantile osteopetrosis with distal renal tubular acidosis.
PG  - 115-21
AB  - 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 CA2, 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. 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 CA2. In the other, CAII levels were 
      normal despite a similar clinical picture, and we excluded defects in CA2. In 
      this kindred, two separate recessive disorders are penetrant, each affecting a 
      different, tissue specific subunit of the vacuolar proton pump (H(+)-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 TCIRG1, which encodes an osteoclast specific isoform of subunit a of the 
      H(+)-ATPase, while the dRTA is associated with a homozygous mutation in ATP6V1B1, 
      encoding the kidney specific B1 subunit of H(+)-ATPase. 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(+)-ATPase that have opposite effects on 
      bone density, but which have only recently been determined to possess tissue 
      specific isoforms.
FAU - Borthwick, K J
AU  - Borthwick KJ
AD  - Department of Medical Genetics, Cambridge University, Cambridge, UK.
FAU - Kandemir, N
AU  - Kandemir N
FAU - Topaloglu, R
AU  - Topaloglu R
FAU - Kornak, U
AU  - Kornak U
FAU - Bakkaloglu, A
AU  - Bakkaloglu A
FAU - Yordam, N
AU  - Yordam N
FAU - Ozen, S
AU  - Ozen S
FAU - Mocan, H
AU  - Mocan H
FAU - Shah, G N
AU  - Shah GN
FAU - Sly, W S
AU  - Sly WS
FAU - Karet, F E
AU  - Karet FE
LA  - eng
PT  - Case Reports
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
PL  - England
TA  - J Med Genet
JT  - Journal of medical genetics
JID - 2985087R
RN  - 0 (Isoenzymes)
RN  - 9007-49-2 (DNA)
RN  - EC 3.6.3.14 (Proton-Translocating ATPases)
RN  - EC 4.2.1.- (Carbonic Anhydrase II)
SB  - IM
MH  - Acidosis, Renal Tubular/enzymology/*genetics
MH  - Base Sequence
MH  - Carbonic Anhydrase II/*deficiency/genetics
MH  - Child
MH  - Child, Preschool
MH  - Consanguinity
MH  - DNA/chemistry/genetics
MH  - DNA Mutational Analysis
MH  - Family Health
MH  - Fatal Outcome
MH  - Female
MH  - Genotype
MH  - Humans
MH  - Infant
MH  - Isoenzymes/genetics
MH  - Male
MH  - Mutation
MH  - Osteopetrosis/enzymology/*genetics
MH  - Pedigree
MH  - Proton-Translocating ATPases/genetics
PMC - PMC1735376
EDAT- 2003/02/05 04:00
MHDA- 2003/03/11 04:00
PMCR- 2006/02/01
CRDT- 2003/02/05 04:00
PHST- 2003/02/05 04:00 [pubmed]
PHST- 2003/03/11 04:00 [medline]
PHST- 2003/02/05 04:00 [entrez]
PHST- 2006/02/01 00:00 [pmc-release]
AID - 10.1136/jmg.40.2.115 [doi]
PST - ppublish
SO  - J Med Genet. 2003 Feb;40(2):115-21. doi: 10.1136/jmg.40.2.115.