Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0025362 (mental retardation)
 15,878 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Clinical manifestations in patients with carbonic anhydrase (CA) II deficiency include osteopetrosis, renal tubular acidosis, and cerebral calcification. Of the 39 reported cases of the carbonic anhydrase II deficiency syndrome, 72% were patients from North African and Middle Eastern countries, most, if not all, of whom were of Arabic descent. We have analyzed DNAs from members of six unrelated Arabic kindreds and found five to be homozygous and one heterozygous for a novel splice junction (donor site) mutation at the 5' end of intron 2. These findings suggest that a common "Arabic" mutation may be the predominant cause of CA II deficiency in this region. The mutation introduces a new Sau3A1 restriction site which allows polymerase chain reaction (PCR)-based diagnosis of this mutation that should be useful in diagnosis, carrier detection, and prenatal diagnosis. The presence of mental retardation and relative infrequency of skeletal fractures distinguish the clinical course of the patients with the Arabic mutation from those of the American and Belgian patients with the His 107-->Tyr mutation.
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PMID:A splice junction mutation in intron 2 of the carbonic anhydrase II gene of osteopetrosis patients from Arabic countries. 130 35

Deficiency of carbonic anhydrase II (carbonate hydro-lyase, EC 4.2.1.1) is the primary defect in the syndrome of osteopetrosis, renal tubular acidosis, and cerebral calcification. In this report we describe the molecular basis for carbonic anhydrase II deficiency in the American family in which the association of carbonic anhydrase II deficiency with this syndrome was first recognized. The three affected siblings from this family are compound heterozygotes, each having inherited two different mutations in the structural gene for carbonic anhydrase II. The paternal mutation is a splice acceptor site mutation at the 3' end of intron 5. The maternal mutation is a missense mutation in exon 3 that substitutes a tyrosine for histidine-107. We show that the mutant enzyme expressed in bacteria from the cDNA containing the His-107----Tyr mutation has detectable, though greatly reduced, activity. We suggest that residual activity of the His-107----Tyr mutant enzyme may explain the absence of mental retardation and the relatively mild phenotype of carbonic anhydrase II deficiency in affected members of this family.
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PMID:Molecular basis of human carbonic anhydrase II deficiency. 154 74

Carbonic anhydrase II (CA II) deficiency in man is an autosomal recessive disorder manifest by osteopetrosis, renal tubular acidosis, and cerebral calcification. Other features include growth failure and mental retardation. Complications of the osteopetrosis include frequent bone fractures, cranial nerve compression symptoms, and dental malocclusion. The anemia and leukopenia seen in the recessive, lethal infantile form of osteopetrosis are not seen in CA II deficient patients. The renal tubular acidosis usually includes both proximal and distal components. Symptoms of metabolic acidosis respond to therapy, but no specific treatment is available for the osteopetrosis or cerebral calcification. We review here the role of carbonic anhydrases in bone resorption and renal acidification, and discuss clinical features and laboratory findings which distinguish CA II deficiency from other disorders producing osteopetrosis, renal tubular acidosis, or brain calcification. Methods to evaluate patients with pure proximal renal tubular acidosis for deficiency of CA IV are also discussed.
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PMID:Evaluation of carbonic anhydrase isozymes in disorders involving osteopetrosis and/or renal tubular acidosis. 195 22

Four new Saudi Arabian cases of the carbonic anhydrase II deficiency syndrome from two families are described. This autosomal recessive syndrome includes osteopetrosis with renal tubular acidosis and cerebral calcification. Additional features are mental retardation, growth failure, typical facial appearance, and abnormal teeth. Two patients showed evidence of restrictive lung disease, a finding not previously described. One of the patients reported represents the first neonate reported to be affected with this syndrome. Intrauterine growth was normal, but metabolic acidosis was already evident in the neonatal period. Radiographic evidence of osteopetrosis was probably absent at birth but appeared during the late neonatal period. Carbonic anhydrase II deficiency was demonstrated in erythrocyte hemolysates from the older two siblings of this neonate, and a 50% normal level of carbonic anhydrase II was demonstrated in the erythrocyte hemolysate from their father.
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PMID:Carbonic anhydrase II deficiency syndrome: recessive osteopetrosis with renal tubular acidosis and cerebral calcification. 308 69

Four children are described from three Saudi Arabian families suffering from osteopetrosis, distal renal tubular acidosis and cerebral calcification associated clinically with mental retardation, stunted growth, abnormal teeth and a similar facial appearance. The syndrome is inherited as an autosomal recessive. The growth retardation is attributed to renal tubular acidosis but no metabolic link is evident between its other major features, and the fundamental defect is unknown. The disorder is radiologically indistinguishable from the classical recessive (malignant) and dominant (benign) forms of osteopetrosis but its other characteristics establish it as a separate disease entity.
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PMID:Marble brain disease: recessive osteopetrosis, renal tubular acidosis and cerebral calcification in three Saudi Arabian families. 735 36

Three Japanese patients with carbonic anhydrase II (CAII) deficiency from three families were described. The parents of one patient were unrelated, the parents of each of the other two patients were first cousins. All the patients had renal tubular acidosis, osteopetrosis, symmetrical cerebral calcification and mental retardation. They exhibited poor activity and poor appetite in the neonatal period, and then developed psychomotor retardation. Two of them were diagnosed as having osteopetrosis at 10 months and 36 years of age, respectively, and the other as having osteomalacia at 28 years of age. All patients had recurrent episodes of muscle weakness. The CAII enzyme activity and protein levels in red blood cells in each of the three patients were deficient. Their parents exhibited approximately 50% normal levels of CAII activity and protein. This is the first report of patients with CAII deficiency in the Japanese population.
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PMID:Carbonic anhydrase II deficiency in three unrelated Japanese patients. 812 74

We describe a 16-year-old female with persistent isolated proximal renal tubular acidosis, cerebral calcification, mental retardation, band keratopathy, cataracts, glaucoma and short stature. Severe metabolic acidosis and hypokalaemia were linked to an abnormally low renal threshold for bicarbonate reabsorption (8 mmol/l). Maximal rates of urinary excretion of titratable acid and ammonium were normal; erythrocyte carbonic anhydrase II was normal. This rare case represents a systemic disease with a distinct clinical entity which may be transmitted by autosomal recessive inheritance.
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PMID:Persistent isolated proximal renal tubular acidosis--a systemic disease with a distinct clinical entity. 814 30

A splice junction mutation at the exon 2-intron 2 boundary of the carbonic anhydrase II (CA II) gene was previously shown to be the unique mutation underlying the CA II deficiency syndrome in patients of Arab descent. Fourteen Tunisian (Maghrebian) families with a history of osteopetrosis, renal tubular acidosis, mental retardation, and CA II deficiency were studied to test the hypothesis that the mutation, found in all 24 patients, derived from a common ancestor originating in the Arabic Peninsula. A filiation study permitted us to trace these families back to a common Arabic tribe that settled in the Maghreb in the tenth century, indicating a common ethnic origin for these families. Segregation of the mutation with a TaqI biallelic restriction site polymorphism upstream of the CA II gene was studied by sequence-tagged site analysis in all the family members. These studies showed cosegregation of the Taq (-) allele with the mutation in 12 families out of 14. This observation supports a founder effect to explain the common CA II deficiency allele in this population. In the remaining two families, a genomic recombination or gene conversion occurred between the TaqI restriction marker and the mutation causing the disease. The relatively high recombination frequency suggests the presence of a hot spot for recombination or gene conversion at the CA II locus.
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PMID:Carbonic anhydrase II (CA II) deficiency in Maghrebian patients: evidence for founder effect and genomic recombination at the CA II locus. 915 Jul 31

Carbonic anhydrase (CA) II deficiency is characterized by osteopetrosis, renal tubular acidosis, cerebral calcification, and usually severe mental retardation. We describe an Italian boy with this disease whose mental retardation was relatively mild and whose renal tubular acidosis had only a distal component. A novel mutation of a gt-->tt change of splice donor site at the 5' end of intron 6 was demonstrated. Comparison of this patient with two previous Italian families with different mutations illustrates the clinical and molecular heterogeneity of this disease. The identification of the mutation in this family provided the opportunity for prenatal diagnosis in a subsequent pregnancy.
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PMID:Clinical and molecular heterogeneity in carbonic anhydrase II deficiency and prenatal diagnosis in an Italian family. 958 Jul 77

Permanent isolated proximal renal tubular acidosis (pRTA) with ocular abnormalities is a systemic disease involving short stature, isolated pRTA, mental retardation, and ocular abnormalities. Kidney Na+/HCO3- cotransporter (kNBC1) cDNA from peripheral lymphocytes from a patient with permanent isolated pRTA and bilateral glaucoma was screened, and a novel homozygous mutation, namely a cytosine-to-thymine transition at nucleotide 234, which resulted in the formation of a stop codon at codon 29, was identified. This homozygous mutation, Q29X, was identified in the unique 5'-end of the kNBC1 gene (SLC4A4) of the patient. Cosegregation of this Q29X mutation with the disease and heterozygosity in the parents of the affected patient were observed. The absence of this mutation in 156 alleles from 78 Japanese individuals indicates that this mutation is directly related to the disease and is not a common DNA sequence polymorphism. This nonsense mutation predicts a truncated kNBC1 protein that lacks the 1007 amino acids of the carboxyl-terminus, and the effect on kNBC1 cotransport activity is likely to be a loss of function. In contrast, the pancreatic Na+/HCO3- cotransporter of the patient is not likely to be affected by this nonsense mutation. These results have implications for understanding the role of kNBC1 in the pathophysiologic processes of pRTA associated with ocular abnormalities and mental retardation.
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PMID:Novel nonsense mutation in the Na+/HCO3- cotransporter gene (SLC4A4) in a patient with permanent isolated proximal renal tubular acidosis and bilateral glaucoma. 1127 32


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