CA2 – Autosomal Recessive Osteopetrosis 3

Carbonic anhydrase II (CAII), encoded by CA2, catalyzes reversible hydration of CO₂ crucial for osteoclast and renal tubular function. Biallelic CA2 variants underlie autosomal recessive osteopetrosis type 3 (CA II deficiency syndrome), characterized by osteosclerosis, renal tubular acidosis (RTA), and intracerebral calcification.

CA2-related osteopetrosis 3 exhibits autosomal recessive inheritance with ≥19 probands reported, including seven Caribbean Hispanic patients (PMID:8128957) and three Japanese patients (PMID:8127074). Segregation analysis has documented affected sibling pairs confirming co-segregation in multiple consanguineous and non-consanguineous kindreds (2 additional affected relatives).

The variant spectrum encompasses frameshift, splice-site, and missense mutations. Recurrent loss-of-function alleles include the c.143_146del (p.Ser48PhefsTer9) homozygous frameshift in a Middle Eastern cohort (PMID:31061753). Other pathogenic changes include c.319C>T (p.His107Tyr) and splice-site variants disrupting enzyme stability and expression.

Functional studies demonstrate severely reduced CAII activity in patient-derived cells and heterologous systems. The c.143_146del mutant yields a truncated, insoluble enzyme with <5% activity and accelerated degradation in COS cells (PMID:8128957). Site-directed mutagenesis of active-site residues further elucidates haploinsufficiency and impaired proton transfer.

Clinically, CA II deficiency presents with variable severity of osteopetrosis (HP:0011002), mixed RTA (HP:0001947), cerebral calcification (HP:0002514), and intellectual disability (HP:0001249). Phenotypic heterogeneity correlates with residual enzyme function, notably milder neurodevelopmental features in certain splice-site mutant carriers (PMID:9580777).

Genotype–phenotype correlations support prenatal genetic testing and early alkali therapy to mitigate metabolic acidosis and growth complications (PMID:15300855). The breadth of CA2 allelic heterogeneity and functional concordance firmly establishes a definitive gene–disease relationship.

Key Take-home: Early molecular diagnosis of CA2 deficiency guides targeted management of RTA and osteopetrosis, improving long-term outcomes.

References

• American journal of human genetics • 1994 • Carbonic anhydrase II deficiency: single-base deletion in exon 7 is the predominant mutation in Caribbean Hispanic patients. PMID:8128957
• Journal of inherited metabolic disease • 1993 • Carbonic anhydrase II deficiency in three unrelated Japanese patients. PMID:8127074
• The Journal of pediatrics • 1998 • Clinical and molecular heterogeneity in carbonic anhydrase II deficiency and prenatal diagnosis in an Italian family. PMID:9580777
• Journal of pediatric genetics • 2019 • Report of Another Mutation Proven Case of Carbonic Anhydrase II Deficiency. PMID:31061753
• Journal of medical genetics • 2003 • A phenocopy of CAII deficiency: a novel genetic explanation for inherited infantile osteopetrosis with distal renal tubular acidosis. PMID:12566520
• Human mutation • 2004 • Carbonic anhydrase II deficiency syndrome (osteopetrosis with renal tubular acidosis and brain calcification): novel mutations in CA2 identified by direct sequencing expand the opportunity for genotype-phenotype correlation. PMID:15300855

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