FAMILIAL HYPOCALCIURIC HYPERCALCEMIA AND NEONATAL SEVERE HYPERPARATHYROIDISM - EFFECTS OF MUTANT-GENE DOSAGE ON PHENOTYPE

被引:205
作者
POLLAK, MR
CHOU, YHW
MARX, SJ
STEINMANN, B
COLE, DEC
BRANDI, ML
PAPAPOULOS, SE
MENKO, FH
HENDY, GN
BROWN, EM
SEIDMAN, CE
SEIDMAN, JG
机构
[1] HARVARD UNIV,BRIGHAM & WOMENS HOSP,SCH MED,DEPT MED,BOSTON,MA 02115
[2] HARVARD UNIV,SCH MED,HOWARD HUGHES MED INST,BOSTON,MA 02115
[3] NIDDKD,METAB DIS BRANCH,BETHESDA,MD 20892
[4] UNIV ZURICH,DEPT PEDIAT,CH-8032 ZURICH,SWITZERLAND
[5] DALHOUSIE UNIV,DEPT PEDIAT,HALIFAX B3J 3G9,NS,CANADA
[6] DALHOUSIE UNIV,DEPT PATHOL,HALIFAX B3J 3G9,NS,CANADA
[7] UNIV FLORENCE,DEPT CLIN PHYSIOPATHOL,I-50139 FLORENCE,ITALY
[8] LEIDEN UNIV HOSP,DEPT ENDOCRINOL & METAB DIS,2333 AA LEIDEN,NETHERLANDS
[9] MCGILL UNIV,DEPT MED,MONTREAL H3A 1A1,PQ,CANADA
关键词
GENE DOSAGE; CHROMOSOME; 3Q; CONSANGUINITY; HYPERCALCEMIA; HYPERPARATHYROIDISM;
D O I
10.1172/JCI117062
中图分类号
R-3 [医学研究方法]; R3 [基础医学];
学科分类号
1001 ;
摘要
Neonatal severe hyperparathyroidism is a rare life-threatening disorder characterized by very high serum calcium concentrations (> 15 mg/dl). Many cases have occurred in families with familial hypocalciuric hypercalcemia, a benign condition transmitted as a dominant trait. Among several hypothesized relationships between the two syndromes is the suggestion that neonatal severe hyperparathyroidism is the homozygous form of familial hypocalciuric hypercalcemia. To test this hypothesis, we refined the map location of the gene responsible for familial hypocalciuric hypercalcemia on chromosome 3q. Analyses in 11 families defined marker loci closely linked to the gene responsible for familial hypocalciuric hypercalcemia. These loci were then analyzed in four families with parental consanguinity and offspring with neonatal severe hyperparathyroidism. Each individual who was homozygous for loci that are closely linked to the gene responsible for familial hypocalciuric hypercalcemia had neonatal severe hyperparathyroidism . The calculated odds of linkage between these disorders of > 350,000:1 (lod score = 5.56). We conclude that dosage of the gene defect accounts for these widely disparate clinical phenotypes; a single defective allele causes familial hypocalciuric hypercalcemia, while two defective alleles causes neonatal severe hyperparathyroidism.
引用
收藏
页码:1108 / 1112
页数:5
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