Scientific background:

Summary: Carbonic anhydrase 2 is an enzyme found predominantly in the lumen of renal tubules where it plays an essential role in proton secretion. If defective, mixed type renal tubular acidosis results. The enzyme has an additional function in bone turnover where a defect causes osteopetrosis.

Molecular anatomy: Carbonic anhydrase 2 is predominantly found in kidney and bone.

Pathophysiology: In kidney, it acts intraluminal in both proximal and distal tubules, where it facilitates proton secretion and bicarbonate reabsorption. In bone turnover the enzyme is involved in bone mineral resorption.

Clinical signs: If the function of this enzyme is deficient renal excretion of protons is impaired. Because the enzyme is essential in proximal and distal tubules a mixed type renal tubular acidosis results. The characteristic bone symptom is osteopetrosis.

Interpretation: Interpretation of negativ mutational analysis should take into account the possibility of phenocopy caused by concurrent mutations of TCIRG1 and ATP6V1B1 genes.

Test strategy: Carbonic anhydrase activity can be measured, but the method appears clumsy nowadays.

Methodology:

	clinical test	Method		Genomic sequencing of the entire coding region
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	All known and new missense, nonsense and splice mutations can be detected.
	clinical test	Method		Carrier testing
		Turn-around time		5 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	The test is only specific about the mutation already known in this kindred.
	research test	Method		Gene dosage measurements
		Turn-around time		25 working days
		Effort		little
		Specimen		DNA
		Quality assessment		Internal quality control only
	Of the gene rearrangements, this method is useful to detect large deletions or duplications.

Literature: 

Lotan D et al. (2006) Clinical and molecular findings in a family with the carbonic anhydrase II deficiency syndrome.
Borthwick KJ et al. (2003) A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis.
MAREN TH et al. (1960) A simplified micromethod for the determination of carbonic anhydrase and its inhibitors.
Borthwick KJ et al. (2003) A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis.