Clinical and biochemical phenotypes of adults with monoallelic and biallelic CYP24A1 mutations: evidence of gene dose effect

D. T. O’Keeffe, Peter Tebben, Rajiv Kumar, Ravinder Jit Singh, Y. Wu, R. A. Wermers

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Abstract

Summary: Mutations of the CYP24A1 gene can result in hypercalcemia, hyerpercalciuria, and nephrolithiasis, but disease severity is variable. Clinical and biochemical phenotypes were correlated with gene sequence information in a family with two CYP24A1 mutations. A gene dose effect was apparent with monoallelic mutations demonstrating milder disease manifestations than biallelic mutations. Introduction: The objective was to examine the spectrum of clinical and biochemical phenotypes in a family with monoallelic and biallelic mutations of CYP24A1 after identification of the proband with two mutations of the CYP24A1 gene: (A) p.R396W and (B) E143del-Het. Methods: Clinical and biochemical phenotypes were correlated with CYP24A1 sequence information in the proband and four siblings, a daughter, and two nieces of the proband. The subjects’ medical histories were evaluated, and measurement of serum minerals, vitamin D metabolites, PTH, bone turnover markers, and urinary calcium and sequencing of the CYP24A1 gene were performed. Results: The proband had nephrolithiasis, osteopenia, hypercalcemia, hypercalciuria, elevated serum 1,25(OH)2D, undetectable 24,25(OH)2D, and inappropriately low PTH concentrations. Two subjects with biallelic (A/B) mutations had nephrolithiasis, marked hypercalciuria (583 ± 127 mg/24 h, mean ± SD), compared with five subjects with monoallelic mutations (A or B) with a urine calcium of 265 ± 85 mg/24 h. Two subjects with monoallelic mutations had nephrolithiasis and one had non-PTH dependent hypercalcemia. Five subjects had high 1,25(OH)2D measurements, including three with monoallelic mutations. The 25OHD/24,25(OH)2D ratio, in subjects with biallelic mutations was 291 versus 19.8 in the subjects with monoallelic mutations. Conclusions: In this family, adults with CYP24A1 mutations a gene dose effect is apparent: subjects with biallelic, compound heterozygous mutations (A/B) have a more severe clinical and biochemical phenotype, whereas, subjects with monoallelic mutations demonstrate milder disease manifestations which are not easily characterized through biochemical assessment.

Original languageEnglish (US)
Pages (from-to)1-5
Number of pages5
JournalOsteoporosis International
DOIs
StateAccepted/In press - Apr 29 2016

Fingerprint

Phenotype
Mutation
Genes
Nephrolithiasis
Hypercalcemia
Hypercalciuria
Vitamin D3 24-Hydroxylase
Calcium
Bone Remodeling
Metabolic Bone Diseases
Serum
Vitamin D
Minerals
Urine

Keywords

  • CYP24A1
  • Genetic
  • Hypercalcemia
  • Nephrolithiasis
  • Vitamin D

ASJC Scopus subject areas

  • Endocrinology, Diabetes and Metabolism

Cite this

@article{a4276c6b07c84fc79b103ac08f37d01c,
title = "Clinical and biochemical phenotypes of adults with monoallelic and biallelic CYP24A1 mutations: evidence of gene dose effect",
abstract = "Summary: Mutations of the CYP24A1 gene can result in hypercalcemia, hyerpercalciuria, and nephrolithiasis, but disease severity is variable. Clinical and biochemical phenotypes were correlated with gene sequence information in a family with two CYP24A1 mutations. A gene dose effect was apparent with monoallelic mutations demonstrating milder disease manifestations than biallelic mutations. Introduction: The objective was to examine the spectrum of clinical and biochemical phenotypes in a family with monoallelic and biallelic mutations of CYP24A1 after identification of the proband with two mutations of the CYP24A1 gene: (A) p.R396W and (B) E143del-Het. Methods: Clinical and biochemical phenotypes were correlated with CYP24A1 sequence information in the proband and four siblings, a daughter, and two nieces of the proband. The subjects’ medical histories were evaluated, and measurement of serum minerals, vitamin D metabolites, PTH, bone turnover markers, and urinary calcium and sequencing of the CYP24A1 gene were performed. Results: The proband had nephrolithiasis, osteopenia, hypercalcemia, hypercalciuria, elevated serum 1,25(OH)2D, undetectable 24,25(OH)2D, and inappropriately low PTH concentrations. Two subjects with biallelic (A/B) mutations had nephrolithiasis, marked hypercalciuria (583 ± 127 mg/24 h, mean ± SD), compared with five subjects with monoallelic mutations (A or B) with a urine calcium of 265 ± 85 mg/24 h. Two subjects with monoallelic mutations had nephrolithiasis and one had non-PTH dependent hypercalcemia. Five subjects had high 1,25(OH)2D measurements, including three with monoallelic mutations. The 25OHD/24,25(OH)2D ratio, in subjects with biallelic mutations was 291 versus 19.8 in the subjects with monoallelic mutations. Conclusions: In this family, adults with CYP24A1 mutations a gene dose effect is apparent: subjects with biallelic, compound heterozygous mutations (A/B) have a more severe clinical and biochemical phenotype, whereas, subjects with monoallelic mutations demonstrate milder disease manifestations which are not easily characterized through biochemical assessment.",
keywords = "CYP24A1, Genetic, Hypercalcemia, Nephrolithiasis, Vitamin D",
author = "O’Keeffe, {D. T.} and Peter Tebben and Rajiv Kumar and Singh, {Ravinder Jit} and Y. Wu and Wermers, {R. A.}",
year = "2016",
month = "4",
day = "29",
doi = "10.1007/s00198-016-3615-6",
language = "English (US)",
pages = "1--5",
journal = "Osteoporosis International",
issn = "0937-941X",
publisher = "Springer London",

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TY - JOUR

T1 - Clinical and biochemical phenotypes of adults with monoallelic and biallelic CYP24A1 mutations

T2 - evidence of gene dose effect

AU - O’Keeffe, D. T.

AU - Tebben, Peter

AU - Kumar, Rajiv

AU - Singh, Ravinder Jit

AU - Wu, Y.

AU - Wermers, R. A.

PY - 2016/4/29

Y1 - 2016/4/29

N2 - Summary: Mutations of the CYP24A1 gene can result in hypercalcemia, hyerpercalciuria, and nephrolithiasis, but disease severity is variable. Clinical and biochemical phenotypes were correlated with gene sequence information in a family with two CYP24A1 mutations. A gene dose effect was apparent with monoallelic mutations demonstrating milder disease manifestations than biallelic mutations. Introduction: The objective was to examine the spectrum of clinical and biochemical phenotypes in a family with monoallelic and biallelic mutations of CYP24A1 after identification of the proband with two mutations of the CYP24A1 gene: (A) p.R396W and (B) E143del-Het. Methods: Clinical and biochemical phenotypes were correlated with CYP24A1 sequence information in the proband and four siblings, a daughter, and two nieces of the proband. The subjects’ medical histories were evaluated, and measurement of serum minerals, vitamin D metabolites, PTH, bone turnover markers, and urinary calcium and sequencing of the CYP24A1 gene were performed. Results: The proband had nephrolithiasis, osteopenia, hypercalcemia, hypercalciuria, elevated serum 1,25(OH)2D, undetectable 24,25(OH)2D, and inappropriately low PTH concentrations. Two subjects with biallelic (A/B) mutations had nephrolithiasis, marked hypercalciuria (583 ± 127 mg/24 h, mean ± SD), compared with five subjects with monoallelic mutations (A or B) with a urine calcium of 265 ± 85 mg/24 h. Two subjects with monoallelic mutations had nephrolithiasis and one had non-PTH dependent hypercalcemia. Five subjects had high 1,25(OH)2D measurements, including three with monoallelic mutations. The 25OHD/24,25(OH)2D ratio, in subjects with biallelic mutations was 291 versus 19.8 in the subjects with monoallelic mutations. Conclusions: In this family, adults with CYP24A1 mutations a gene dose effect is apparent: subjects with biallelic, compound heterozygous mutations (A/B) have a more severe clinical and biochemical phenotype, whereas, subjects with monoallelic mutations demonstrate milder disease manifestations which are not easily characterized through biochemical assessment.

AB - Summary: Mutations of the CYP24A1 gene can result in hypercalcemia, hyerpercalciuria, and nephrolithiasis, but disease severity is variable. Clinical and biochemical phenotypes were correlated with gene sequence information in a family with two CYP24A1 mutations. A gene dose effect was apparent with monoallelic mutations demonstrating milder disease manifestations than biallelic mutations. Introduction: The objective was to examine the spectrum of clinical and biochemical phenotypes in a family with monoallelic and biallelic mutations of CYP24A1 after identification of the proband with two mutations of the CYP24A1 gene: (A) p.R396W and (B) E143del-Het. Methods: Clinical and biochemical phenotypes were correlated with CYP24A1 sequence information in the proband and four siblings, a daughter, and two nieces of the proband. The subjects’ medical histories were evaluated, and measurement of serum minerals, vitamin D metabolites, PTH, bone turnover markers, and urinary calcium and sequencing of the CYP24A1 gene were performed. Results: The proband had nephrolithiasis, osteopenia, hypercalcemia, hypercalciuria, elevated serum 1,25(OH)2D, undetectable 24,25(OH)2D, and inappropriately low PTH concentrations. Two subjects with biallelic (A/B) mutations had nephrolithiasis, marked hypercalciuria (583 ± 127 mg/24 h, mean ± SD), compared with five subjects with monoallelic mutations (A or B) with a urine calcium of 265 ± 85 mg/24 h. Two subjects with monoallelic mutations had nephrolithiasis and one had non-PTH dependent hypercalcemia. Five subjects had high 1,25(OH)2D measurements, including three with monoallelic mutations. The 25OHD/24,25(OH)2D ratio, in subjects with biallelic mutations was 291 versus 19.8 in the subjects with monoallelic mutations. Conclusions: In this family, adults with CYP24A1 mutations a gene dose effect is apparent: subjects with biallelic, compound heterozygous mutations (A/B) have a more severe clinical and biochemical phenotype, whereas, subjects with monoallelic mutations demonstrate milder disease manifestations which are not easily characterized through biochemical assessment.

KW - CYP24A1

KW - Genetic

KW - Hypercalcemia

KW - Nephrolithiasis

KW - Vitamin D

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U2 - 10.1007/s00198-016-3615-6

DO - 10.1007/s00198-016-3615-6

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JO - Osteoporosis International

JF - Osteoporosis International

SN - 0937-941X

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