4A-S4-3
MOLECULAR
PATHOGENESIS OF CONGENITAL RENAL TUBULAR ACIDOSIS Takashi Igarashi Department of Pediatrics, Faculty of Medicine, The
University of Tokyo, Japan Renal
tubular acidosis (RTA) is a clinical syndrome of disordered renal
acidification in which the kidney fails to maintain a normal plasma
concentration of HCO3- in the setting of a normal rate of acid load from
diet and metabolism. Most of
the RTA in children are hereditary. Hereditary RTA can be classified into
several groups on clinical and pathophysiological grounds. Recent progress of molecular
biological analyses is unraveling the molecular basis of hereditary
RTA. Mutations in the kidney
type Na+/HCO3- cotransporter gene (SLC4A4) cause permanent isolated
proximal RTA with ocular abnormalities. Mutations in carbonic anhydrase II gene lead to
osteopetrosis, RTA (proximal RTA, distal RTA or combined proximal and
distal RTA), cerebral calcification, and mental retardation. Mutations in the gene (SLC4A1)
encoding the Cl-/HCO3- exchanger produce autosomal dominant distal
RTA. However, mutations
in SLC4A1 also link to a recessive syndrome of distal RTA with hemolytic
anemia (Southeast Asian ovalocytosis) in Thailand. The phenotype of this distal RTA in
Thailand is very close to that of autosomal dominant distal RTA in other
countries. In contrast,
autosomal recessive distal RTA, which is phenotypically heterogeneous, is a
more severe disorder than autosomal dominant distal RTA. Mutations in ATP6B1, the B1-subunit
of the apical H+-ATPase mediating distal nephron acid secretion, cause
distal RTA with progressive bilateral sensorineural hearing loss. Moreover, mutations in ATP6N1B,
encoding a tubular apical H+-ATPase 116-kD subunit, is identified to lead
to dRTA with preserved hearing.
These results help to understand further the molecular basis of
hereditary RTA and characterize the clinical and genetic manifestations of
the disorders.