Functional deletion of the calcium-sensing receptor in a case of neonatal severe hyperparathyroidism.

[familial hypocalciuric hypercalcemia]

Heterozygous inactivating mutations of the calcium-sensing receptor (CaR ) cause familial hypocalciuric hypercalcemia , whereas homozygous or compound heterozygous inactivating mutations normally cause neonatal severe hyperparathyroidism . In a case of neonatal severe hyperparathyroidism characterized by moderately severe hypercalcemia and very high PTH levels , coupled with evidence of hyperparathyroidism and effects on brain development not previously demonstrated , we detected point mutations on separate alleles of the CaR , resulting in premature stop codon substitutions at G 94 and R 648 . This led to severely truncated receptors and an effective so -called knockout of functional CaR . FLAG-tagged , truncated receptors were expressed in HEK 293 cells for functional analysis . Confocal microscopy demonstrated cytoplasmic localization of the G 94 stop receptor , whereas the R 648 stop receptor was present both in the cytoplasm and associated with the cell membrane . Only the R 648 stop receptor could be detected by Western analysis . Functional assays in which R 648 stop and wild-type receptor were cotransfected into HEK 293 cells demonstrated a reduction in wild-type Ca (2 +)-responsiveness by the R 648 stop receptor , even at physiological Ca (2 +) levels , thus simulating familial hypocalciuric hypercalcemia in relatives of the infant who were heterozygous for the R 648 stop mutation . The R 648 stop receptor alone was nonresponsive to Ca (2 +). This case contributes to our understanding of the clinical manifestation of a CaR knockout .

Diseases
Validation

Diseases presenting "functional analysis" symptom

canavan disease

child syndrome

congenital adrenal hyperplasia

cowden syndrome

cystinuria

familial hypocalciuric hypercalcemia

hirschsprung disease

holt-oram syndrome

homocystinuria without methylmalonic aciduria

hydrocephalus with stenosis of the aqueduct of sylvius

kallmann syndrome

krabbe disease

pendred syndrome

primary effusion lymphoma

triple a syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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