Carbonic anhydrase II deficiency: Single-base deletion in exon 7 is the predominant mutation in Caribbean Hispanic patients

Journal Article · Fri Apr 01 04:00:00 EST 1994 · American Journal of Human Genetics; (United States)

OSTI ID:7285357

Hu, P Y; Ernst, A R; Sly, W S ^[1]; Venta, P J ^[2]; Skaggs, L A; Tashian, R E ^[3]

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1. St. Louis Univ. School of Medicine, MO (United States)
2. Michigan State Univ., East Lansing, MI (United States)
3. Univ. of Michigan Medical School, Ann Arbor, MI (United States)

To date, three different structural gene mutations have been identified in patients with carbonic anhydrase II deficiency (osteopetrosis with renal tubular acidosis and cerebral calcification). These include a missense mutation (H107Y) in two families, a splice junction mutation in intron 5 in one of these families, and a splice junction mutation in intron 2 for which many Arabic patients are homozygous. The authors report here a novel mutation for which carbonic anhydrase II-deficient patients from seven unrelated Hispanic families were found to be homozygous. The proband was a 2 1/2-year-old Hispanic girl of Puerto Rican ancestry who was unique clinically, in that she had no evidence of renal tubular acidosis, even though she did have osteopetrosis, developmental delay, and cerebral calcification. She proved to be homozygous for a single-base deletion in the coding region of exon 7 that produces a frameshift that changes the next 12 amino acids before leading to chain termination and that also introduces a new MaeIII restriction site. The 27-kD truncated enzyme produced when the mutant cDNA was expressed in COS cells was enzymatically inactive, present mainly in insoluble aggregates, and detectable immunologically at only 5% the level of the 29-kD normal carbonic anhydrase II expressed from the wild-type cDNA. Metabolic labeling revealed that this 27-kD mutant protein has an accelerated rate of degradation. Six subsequent Hispanic patients of Caribbean ancestry, all of whom had osteopetrosis and renal tubular acidosis but who varied widely in clinical severity, were found to be homozygous for the same mutation. These findings identify a novel mutation common to Hispanic patients from the Caribbean islands and provide a ready means for PCR-based diagnosis of the [open quotes]Hispanic mutation.[close quotes] The basis for their phenotypic variability is not yet clear. 15 refs., 5 figs., 1 tab.

• OSTI ID: 7285357
• Journal Information: American Journal of Human Genetics; (United States), Journal Name: American Journal of Human Genetics; (United States) Vol. 54:4; ISSN AJHGAG; ISSN 0002-9297
• Country of Publication: United States
• Language: English

Related Subjects

550400* -- Genetics
550900 -- Pathology
59 BASIC BIOLOGICAL SCIENCES
ANIMAL TISSUES
BODY
BONE TISSUES
BRAIN
CARBON-OXYGEN LYASES
CARBONIC ANHYDRASE
CENTRAL NERVOUS SYSTEM
CEREBRAL CORTEX
CEREBRUM
CONNECTIVE TISSUE
DISEASES
ENZYMES
GENE MUTATIONS
HEREDITARY DISEASES
HYDRO-LYASES
KIDNEYS
LYASES
METABOLIC DISEASES
MUTATIONS
NERVOUS SYSTEM
ORGANIC COMPOUNDS
ORGANS
PROTEINS
TISSUES