Expression of three different mutations in the arginine vasopressin gene suggests genotype-phenotype correlation in familial neurohypophyseal diabetes insipidus kindreds.
OBJECTIVE
The autosomal dominant form of familial neurohypophyseal diabetes insipidus (adFNDI) is a rare disease characterized by a severe and progressive deficiency of AVP secondary to mutations in the gene encoding the AVP precursor. Whereas a number of studies have investigated the pathogenetic mechanisms behind the disease only few studies have included detailed clinical characterization of the affected patients, thereby making genotype-phenotype correlations difficult. The aims of the present study were to investigate the cellular effects of three different adFNDI mutations (A19T, L81P and C110X) by heterologous expression in a neurogenic cell line and to correlate these findings to the corresponding clinical phenotype as determined by extensive clinical tests.


RESULTS
The clinical studies showed a later age of onset in the family carrying the A19T mutation (3.4 years, range 2-9 years) compared with families with the L81P and C110X mutations [0.75 year, range 0.5-1 year and 1.0 year (n = 1), respectively]. No other differences could be demonstrated in the clinical phenotype between families. Expression studies showed that each of the three mutant genes caused significant reduction of the amount of immunoreactive AVP in the cell culture medium and severe impairment of the intracellular trafficking and processing of the AVP prohormone, supporting the disease causing nature of all three mutations. However, the A19T mutation was associated with some capacity for processing and trafficking consistent with the clinical observations. Immunoflourescence studies provided evidence of reticular accumulation of protein within the ER in the A19T and C110X mutants but a unique accumulation of much larger aggregates in the L81P, which were localized both within and immediately outside the ER.


CONCLUSIONS
The study suggests a genotype-phenotype correlation with regard to age of onset of diabetes insipidus symptoms and provides support by expression studies.
Siggaard
Charlotte
C
Department of Pediatrics, Aarhus University Hospital, Skejby Sygehus, Aarhus, Denmark.
Christensen
Jane H
JH
Corydon
Thomas J
TJ
Rittig
Søren
S
Robertson
Gary L
GL
Gregersen
Niels
N
Bolund
Lars
L
Pedersen
Erling B
EB
D000293:Adolescent; D000328:Adult; D017668:Age of Onset; D000368:Aged; D001127:Arginine Vasopressin / Q000235:genetics*; D045744:Cell Line, Tumor; D002648:Child; D020790:Diabetes Insipidus, Neurogenic / Q000235:genetics*; D005192:Family Health; D005260:Female; D005786:Gene Expression Regulation / Q000235:genetics; D005838:Genotype; D006801:Humans; D047468:Immunoprecipitation / Q000379:methods; D008297:Male; D018613:Microscopy, Confocal / Q000379:methods; D008875:Middle Aged; D009154:Mutation; D010641:Phenotype; D011506:Proteins / Q000032:analysis
D011506:Proteins; D001127:Arginine Vasopressin