Molekulargenetische Diagnostik
Praxis Dr. Mato Nagel

Renale Störungen der Calciumhomöostase

Eine Reihe von renalen Erkrankungen betreffen den Calciumstoffwechsel. Störungen der Tubulusfunktion können zu erhöhten und erniedrigten Calciumwerten im Blut führen. Meist sind Störungen des Caliumhaushaltes mit Störungen im Parathormonspiegel oder im Vitamin D-Stoffwechsel verknüpft.

Pathogenese

Regulation der Calcium-Balance

Bei der Calcium-Balance spielt das Parathormon (PTH) eine entscheidende Rolle. Über den Calcium-Sensing-Rezeptor wird die aktuelle Serumkonzentration gemessen und die PTH-Sekretion entsprechend angepasst. Die Grafik zeigt über welche Mechanismen die extrazelluläre Calcium-Konzentration erhöht wird. Dazu gehören die renale Reabsorption und die Knochenresorption. Die vermehrte enterale Calcium-Absorption wird vor allem über eine Aktivierung von Vitamin D erreicht.

Gliederung

Hereditäre Tubulusfunktionsstörungen der Niere
Erbliche renale Salzverlust-Syndrome
Genetisch bedingte Störungen der proximalen Tubulusfunktion
Liddle-Syndrom
Pseudohypoaldosteronismus
Renale Störungen der Calciumhomöostase
Familiäre hypocalciurische Hypercalciämie Typ 1
CASR
Familiäre hypocalciurische Hypercalciämie Typ 2
GNA11
Familiäre hypocalciurische Hypercalciämie Typ 3
AP2S1
Hypophosphatasie
Adulte Hypophosphatasie
ALPL
Infantile Hypophosphatasie
ALPL
Kindliche Hypophosphatasie
ALPL
Odontohypophosphatasie
ALPL
Infantile Hypercalciämie
CYP24A1
Renale tubuläre Azidose
Renaler Diabetes insipidus

Referenzen:

1.

Heath H et al. (1992) Genetic linkage analysis in familial benign hypercalcemia using a candidate gene strategy. I. Studies in four families.

[^]
2.

Canaff L et al. (2002) Human calcium-sensing receptor gene. Vitamin D response elements in promoters P1 and P2 confer transcriptional responsiveness to 1,25-dihydroxyvitamin D.

[^]
3.

Scillitani A et al. (2004) Blood ionized calcium is associated with clustered polymorphisms in the carboxyl-terminal tail of the calcium-sensing receptor.

[^]
4.

Cole DE et al. (2001) Association between total serum calcium and the A986S polymorphism of the calcium-sensing receptor gene.

[^]
5.

Cole DE et al. (1999) A986S polymorphism of the calcium-sensing receptor and circulating calcium concentrations.

[^]
6.

McMurtry CT et al. (1992) Significant developmental elevation in serum parathyroid hormone levels in a large kindred with familial benign (hypocalciuric) hypercalcemia.

[^]
7.

Cetani F et al. (1999) No evidence for mutations in the calcium-sensing receptor gene in sporadic parathyroid adenomas.

[^]
8.

Chikatsu N et al. (1999) An adult patient with severe hypercalcaemia and hypocalciuria due to a novel homozygous inactivating mutation of calcium-sensing receptor.

[^]
9.

Stock JL et al. (1999) Autosomal dominant hypoparathyroidism associated with short stature and premature osteoarthritis.

[^]
10.

Chikatsu N et al. (2000) Cloning and characterization of two promoters for the human calcium-sensing receptor (CaSR) and changes of CaSR expression in parathyroid adenomas.

[^]
11.

Lienhardt A et al. (2000) A large homozygous or heterozygous in-frame deletion within the calcium-sensing receptor's carboxylterminal cytoplasmic tail that causes autosomal dominant hypocalcemia.

[^]
12.

Carling T et al. (2000) Familial hypercalcemia and hypercalciuria caused by a novel mutation in the cytoplasmic tail of the calcium receptor.

[^]
13.

Hendy GN et al. (2000) Mutations of the calcium-sensing receptor (CASR) in familial hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia.

[^]
14.

Brown EM et al. (2001) Extracellular calcium sensing and extracellular calcium signaling.

[^]
15.

Jap TS et al. (2001) A novel mutation in the calcium-sensing receptor gene in a Chinese subject with persistent hypercalcemia and hypocalciuria.

[^]
16.

Méhes K et al. (1975) Possible dominant inheritance of the idiopathic hypercalcemic syndrome.

[^]
17.

D'Souza-Li L et al. (2001) An acceptor splice site mutation in the calcium-sensing receptor (CASR) gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

[^]
18.

Lienhardt A et al. (2001) Activating mutations of the calcium-sensing receptor: management of hypocalcemia.

[^]
19.

Nagase T et al. (2002) A family of autosomal dominant hypocalcemia with a positive correlation between serum calcium and magnesium: identification of a novel gain of function mutation (Ser(820)Phe) in the calcium-sensing receptor.

[^]
20.

Sato K et al. (2002) Hydrochlorothiazide effectively reduces urinary calcium excretion in two Japanese patients with gain-of-function mutations of the calcium-sensing receptor gene.

[^]
21.

Watanabe S et al. (2002) Association between activating mutations of calcium-sensing receptor and Bartter's syndrome.

[^]
22.

Purroy J et al. (2002) Molecular genetics of calcium sensing in bone cells.

[^]
23.

Kifor O et al. (2003) A syndrome of hypocalciuric hypercalcemia caused by autoantibodies directed at the calcium-sensing receptor.

[^]
24.

Tan YM et al. (2003) Autosomal dominant hypocalcemia: a novel activating mutation (E604K) in the cysteine-rich domain of the calcium-sensing receptor.

[^]
25.

Kos CH et al. (2003) The calcium-sensing receptor is required for normal calcium homeostasis independent of parathyroid hormone.

[^]
26.

Tu Q et al. (2003) Rescue of the skeletal phenotype in CasR-deficient mice by transfer onto the Gcm2 null background.

[^]
27.

Hendy GN et al. (2003) Recurrent familial hypocalcemia due to germline mosaicism for an activating mutation of the calcium-sensing receptor gene.

[^]
28.

Chou YH et al. (1992) The gene responsible for familial hypocalciuric hypercalcemia maps to chromosome 3q in four unrelated families.

[^]
29.

SMITH DW et al. (1959) Idiopathic hypercalcemia; a case report with assays of vitamin D in the serum.

[^]
30.

HOOFT C et al. (1961) Familial incidence of hypercalcaemia. Extreme hypersensitivity to vitamin D in an infant whose father suffered from sarcoidosis.

[^]
31.

KENNY FM et al. (1963) Metabolic studies in a patient with idiopathic hypercalcemia of infancy.

[^]
32.

HILLMAN DA et al. (1964) NEONATAL FAMILIAL PRIMARY HYPERPARATHYROIDISM.

[^]
33.

Pidasheva S et al. (2004) CASRdb: calcium-sensing receptor locus-specific database for mutations causing familial (benign) hypocalciuric hypercalcemia, neonatal severe hyperparathyroidism, and autosomal dominant hypocalcemia.

[^]
34.

Pallais JC et al. (2004) Acquired hypocalciuric hypercalcemia due to autoantibodies against the calcium-sensing receptor.

[^]
35.

Ward BK et al. (2004) Functional deletion of the calcium-sensing receptor in a case of neonatal severe hyperparathyroidism.

[^]
36.

Hough TA et al. (2004) Activating calcium-sensing receptor mutation in the mouse is associated with cataracts and ectopic calcification.

[^]
37.

Rickels MR et al. (2004) Hypocalciuric hypercalcemia and autoantibodies against the calcium-sensing receptor.

[^]
38.

Wystrychowski A et al. (2005) Functional characterization of calcium-sensing receptor codon 227 mutations presenting as either familial (benign) hypocalciuric hypercalcemia or neonatal hyperparathyroidism.

[^]
39.

Miyashiro K et al. (2004) Severe hypercalcemia in a 9-year-old Brazilian girl due to a novel inactivating mutation of the calcium-sensing receptor.

[^]
40.

Pidasheva S et al. (2005) Impaired cotranslational processing of the calcium-sensing receptor due to signal peptide missense mutations in familial hypocalciuric hypercalcemia.

[^]
41.

Adams GB et al. (2006) Stem cell engraftment at the endosteal niche is specified by the calcium-sensing receptor.

[^]
42.

Leech C et al. (2006) Identification of a novel inactivating R465Q mutation of the calcium-sensing receptor.

[^]
43.

Mittelman SD et al. (2006) A hypocalcemic child with a novel activating mutation of the calcium-sensing receptor gene: successful treatment with recombinant human parathyroid hormone.

[^]
44.

Scillitani A et al. (2007) Primary hyperparathyroidism and the presence of kidney stones are associated with different haplotypes of the calcium-sensing receptor.

[^]
45.

Zajickova K et al. (2007) Identification and functional characterization of a novel mutation in the calcium-sensing receptor gene in familial hypocalciuric hypercalcemia: modulation of clinical severity by vitamin D status.

[^]
46.

Nissen PH et al. (2007) Molecular genetic analysis of the calcium sensing receptor gene in patients clinically suspected to have familial hypocalciuric hypercalcemia: phenotypic variation and mutation spectrum in a Danish population.

[^]
47.

Kapoor A et al. (2008) An idiopathic epilepsy syndrome linked to 3q13.3-q21 and missense mutations in the extracellular calcium sensing receptor gene.

[^]
48.

Hannan FM et al. (2010) Comparison of human chromosome 19q13 and syntenic region on mouse chromosome 7 reveals absence, in man, of 11.6 Mb containing four mouse calcium-sensing receptor-related sequences: relevance to familial benign hypocalciuric hypercalcaemia type 3.

[^]
49.

PRATT EL et al. (1947) Hypercalcemia and idiopathic hyperplasia of the parathyroid glands in an infant.

[^]
50.

Lyons J et al. (1990) Two G protein oncogenes in human endocrine tumors.

[^]
51.

Schlingmann KP et al. (2011) Mutations in CYP24A1 and idiopathic infantile hypercalcemia.

[^]
52.

Streeten EA et al. (2011) CYP24A1 mutations in idiopathic infantile hypercalcemia.

[^]
53.

Misselwitz J et al. (1986) [Hypercalcemia following prophylactic vitamin D administration].

[^]
54.

Marx SJ et al. (1985) Familial hypocalciuric hypercalcemia. Mild expression of the gene in heterozygotes and severe expression in homozygotes.

[^]
55.

Law WM et al. (1985) Familial benign hypercalcemia (hypocalciuric hypercalcemia). Clinical and pathogenetic studies in 21 families.

[^]
56.

Weisman Y et al. (1979) Infantile hypercalcemia: a defect in the esterification of 1,25-dihydroxyvitamin D?

[^]
57.

Foley TP et al. (1972) Familial benign hypercalcemia.

[^]
58.

Goldbloom RB et al. (1972) Hereditary parathyroid hyperplasia: a surgical emergency of early infancy.

[^]
59.

Dezateux CA et al. (1984) Neonatal hyperparathyroidism.

[^]
60.

Davies M et al. (1984) Familial hypocalciuric hypercalcaemia: evidence for continued enhanced renal tubular reabsorption of calcium following total parathyroidectomy.

[^]
61.

Arnaud CD et al. (1984) Familial benign hypercalcemia: nature's solution to neonatal hyperparathyroidism?

[^]
62.

Steinmann B et al. (1984) Neonatal severe primary hyperparathyroidism and alkaptonuria in a boy born to related parents with familial hypocalciuric hypercalcemia.

[^]
63.

Menko FH et al. (1984) Familial benign hypercalcaemia (FBH; McK. No. 14598, 1983): linkage studies in a large Dutch family.

[^]
64.

Marx SJ et al. (1978) Divalent cation metabolism. Familial hypocalciuric hypercalcemia versus typical primary hyperparathyroidism.

[^]
65.

Marx SJ et al. (1982) Familial hypocalciuric hypercalcemia: the relation to primary parathyroid hyperplasia.

[^]
66.

Marx SJ et al. (1982) An association between neonatal severe primary hyperparathyroidism and familial hypocalciuric hypercalcemia in three kindreds.

[^]
67.

Marx SJ et al. (1981) The hypocalciuric or benign variant of familial hypercalcemia: clinical and biochemical features in fifteen kindreds.

[^]
68.

Marx SJ et al. (1980) Familial hypocalciuric hypercalcemia: recognition among patients referred after unsuccessful parathyroid exploration.

[^]
69.

Marx SJ et al. (1980) Familial hypocalciuric hypercalcemia.

[^]
70.

Ho C et al. (1995) A mouse model of human familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

[^]
71.

Trump D et al. (1995) Linkage studies in a kindred from Oklahoma, with familial benign (hypocalciuric) hypercalcaemia (FBH) and developmental elevations in serum parathyroid hormone levels, indicate a third locus for FBH.

[^]
72.

Aida K et al. (1995) Familial hypocalciuric hypercalcemia associated with mutation in the human Ca(2+)-sensing receptor gene.

[^]
73.

Janicic N et al. (1995) Insertion of an Alu sequence in the Ca(2+)-sensing receptor gene in familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

[^]
74.

Chou YH et al. (1995) Mutations in the human Ca(2+)-sensing-receptor gene that cause familial hypocalciuric hypercalcemia.

[^]
75.

Garrett JE et al. (1995) Molecular cloning and functional expression of human parathyroid calcium receptor cDNAs.

[^]
76.

Brown EM et al. (1995) Calcium-ion-sensing cell-surface receptors.

[^]
77.

Finegold DN et al. (1994) Preliminary localization of a gene for autosomal dominant hypoparathyroidism to chromosome 3q13.

[^]
78.

Pollak MR et al. (1994) Autosomal dominant hypocalcaemia caused by a Ca(2+)-sensing receptor gene mutation.

[^]
79.

Pollak MR et al. (1993) Mutations in the human Ca(2+)-sensing receptor gene cause familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

[^]
80.

Meeran K et al. (1994) Neonatal primary hyperparathyroidism masked by vitamin D deficiency.

[^]
81.

Pollak MR et al. (1994) Familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism. Effects of mutant gene dosage on phenotype.

[^]
82.

Brown EM et al. (1993) Cloning and characterization of an extracellular Ca(2+)-sensing receptor from bovine parathyroid.

[^]
83.

Clapham DE et al. (1993) Mutations in G protein-linked receptors: novel insights on disease.

[^]
84.

Heath H et al. (1993) Genetic linkage analysis in familial benign (hypocalciuric) hypercalcemia: evidence for locus heterogeneity.

[^]
85.

Janicic N et al. (1995) Mapping of the calcium-sensing receptor gene (CASR) to human chromosome 3q13.3-21 by fluorescence in situ hybridization, and localization to rat chromosome 11 and mouse chromosome 16.

[^]
86.

Li Y et al. (1996) Autoantibodies to the extracellular domain of the calcium sensing receptor in patients with acquired hypoparathyroidism.

[^]
87.

Pearce SH et al. (1995) Calcium-sensing receptor mutations in familial benign hypercalcemia and neonatal hyperparathyroidism.

[^]
88.

Løvlie R et al. (1996) The Ca(2+)-sensing receptor gene (PCAR1) mutation T151M in isolated autosomal dominant hypoparathyroidism.

[^]
89.

Marx SJ et al. (1977) Family studies in patients with primary parathyroid hyperplasia.

[^]
90.

Baron J et al. (1996) Mutations in the Ca(2+)-sensing receptor gene cause autosomal dominant and sporadic hypoparathyroidism.

[^]
91.

Pearce SH et al. (1996) A familial syndrome of hypocalcemia with hypercalciuria due to mutations in the calcium-sensing receptor.

[^]
92.

Bai M et al. (1997) In vivo and in vitro characterization of neonatal hyperparathyroidism resulting from a de novo, heterozygous mutation in the Ca2+-sensing receptor gene: normal maternal calcium homeostasis as a cause of secondary hyperparathyroidism in familial benign hypocalciuric hypercalcemia.

[^]
93.

Bai M et al. (1997) Markedly reduced activity of mutant calcium-sensing receptor with an inserted Alu element from a kindred with familial hypocalciuric hypercalcemia and neonatal severe hyperparathyroidism.

[^]
94.

De Luca F et al. (1997) Sporadic hypoparathyroidism caused by de Novo gain-of-function mutations of the Ca(2+)-sensing receptor.

[^]
95.

Kobayashi M et al. (1997) Two novel missense mutations in calcium-sensing receptor gene associated with neonatal severe hyperparathyroidism.

[^]
96.

Watanabe T et al. (1998) Familial hypoparathyroidism: identification of a novel gain of function mutation in transmembrane domain 5 of the calcium-sensing receptor.

[^]
97.

Lloyd SE et al. (1999) Localization of familial benign hypercalcemia, Oklahoma variant (FBHOk), to chromosome 19q13.

[^]
98.

Okazaki R et al. (1999) A novel activating mutation in calcium-sensing receptor gene associated with a family of autosomal dominant hypocalcemia.

[^]