Journal of Clinical Endocrinology & Metabolism
, doi:10.1210/jc.2004-2000
The Journal of Clinical Endocrinology & Metabolism Vol. 90, No. 7 4388-4393
Copyright © 2005 by The Endocrine Society
Autosomal Dominant Neurohypophyseal Diabetes Insipidus with Linkage to Chromosome 20p13 but without Mutations in the AVP-NPII Gene
Lei Ye,
Xiaoying Li,
Ying Chen,
Hongtao Sun,
Weiqing Wang,
Tingwei Su,
Lei Jiang,
Bin Cui and
Guang Ning
Shanghai Clinical Center for Endocrine and Metabolic Diseases (L.Y., X.L., Y.C., W.W., T.S., L.J., B.C., G.N.), Shanghai Institute of Endocrine and Metabolic Diseases, Ruijin Hospital, Shanghai Second Medical University, Shanghai 200025, People’s Republic of China; Department of Internal Medicine (H.S.), Inner Mongolia University for Nationalities Affiliated Hospital, Inner Mongolia 028000, Mongolia; and Division of Endocrine and Metabolic Diseases (X.L., G.N.), E-Institute of Shanghai Universities, Shanghai 200025, People’s Republic of China
Address all correspondence and requests for reprints to: Guang Ning, M.D., Ph.D., Department of Endocrinology and Metabolism, Ruijin Hospital, Shanghai Second Medical University, Ruijin Er Lu, Shanghai 200025, People’s Republic of China. E-mail: guangning{at}medmail.com.cn.
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Abstract
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Context: Autosomal dominant neurohypophyseal diabetes insipidus (ADNDI) has been known as a rare disorder transmitted as an autosomal dominant trait, characterized by polyuria and polydipsia, and caused by deficient neurosecretion of arginine vasopressin precursor (AVP-NPII). We reported an ADNDI family with linkage to chromosome 20p13 but without mutations in the AVP-NPII gene.
Objective: The objective of this study was to identify the corresponding locus responsible for ADNDI in a family without AVP-NP II gene mutations.
Subjects and Methods: Two families with ADNDI were diagnosed by water deprivation test. The AVP-NPII gene was amplified by PCR and sequenced. A genomewide scan was performed in one family using 400 microsatellite markers covering 22 autosomes.
Results: A 3-bp deletion (1827–1829delAGG) of AVP-NPII gene was identified in the affected individuals in one family. Although no mutations could be detected in the coding, the promoter, and intronic regions of AVP-NPII gene in the other family, a maximum LOD score of 1.202999 (
= 0.00) was obtained at marker D20S889 by genomewide scan, and a 7-cM interval on chromosome 20p13 was defined by fine mapping with markers D20S199–D20S849. Furthermore, the intragenic region that regulates AVP-NPII and oxytocin expression as an enhancer element and the UBCE7IP5 gene that participates in prohormone degradation were sequenced. No alterations could be detected either.
Conclusion: The corresponding locus responsible for ADNDI is possibly heterogeneous regarding the slightly different clinical features in these two families.
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Introduction
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AUTOSOMAL DOMINANT neurohypophyseal diabetes insipidus (ADNDI) is a rare inherited disease caused by primary deficiency of the peptide hormone, arginine vasopressin (AVP), and characterized by polyuria and polydipsia (1). The symptoms usually begin at an early age in the affected individuals and worsen through the lifetime (2). The genetic locus for ADNDI was mapped within or near the AVP-NPII gene, and a defective AVP-NPII allele was identified in an ADNDI family in 1990 (3). To date, more than 40 mutations in the AVP-NPII gene have been identified in ADNDI patients (4, 5, 6, 7, 8, 9). All of those mutations are located in the coding region and alter one or more amino acids that are presumably crucial in removing the signal peptide and/or correctly folding the prohormone in the endoplasmic reticulum. Accumulation of unprocessed prohormones are cytotoxic and lead to degeneration of the vasopressin (VP)-producing neurons, which consequently causes ADNDI (10).
We studied two Chinese families with ADNDI and identified a 3-bp deletion of the AVP-NPII gene in one family. However, in the other family, we could not identify any mutations in the coding, intron, promoter, and the intragenic regions (IGRs) of the AVP-NPII gene even if it is indistinguishable from the family harboring AVP-NPII gene mutation by clinical features and laboratory examinations. Linkage analysis indicated that the corresponding gene(s) responsible for ADNDI in this family was located in a 7-cM interval defined by the short tandem repeats (STR) markers D20S199 and D20S849 on chromosome 20. We proposed that there is locus heterogeneity for ADNDI. It is indispensable to explore this interval to detect the defective gene(s) for ADNDI in this family.
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Subjects and Methods
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Subjects
Two families (families 1 and 2) with ADNDI were studied. Both pedigrees showed an autosomal dominant inheritance pattern of clinical overt DI. In family 1 (Fig. 1A
), the proband (II-5) was a 45-yr-old man who presented with polyuria and polydipsia since he was 1 yr old and the water intake ranging from 15–20 liter/d without 1-desamino-8-D-arginine VP (DDAVP) treatment. Relief of symptoms was followed by exogenous AVP administration. Subjects II-8, III-6, and III-10 also presented with a history of increasing polyuria and polydipsia since childhood. All affected individuals responded to DDAVP therapy with resolution of symptoms. Subject IV-1 was a 14-yr-old boy who presented with enuresis at the age of 11 and a water intake ranging from 3–5 liters/d. The other 11 unaffected individuals have never had symptoms of DI. In Family 2 (Fig. 1B), the proband (II-1) was a 47-yr-old man who developed symptoms of polyuria and polydipsia at the age of 1. The water intake was increased up to a range of 5–10 liter/d at the age of 15, and the symptoms worsened along with lifetime. He presented with thirst and dizziness whenever he did not drink for more than 2 h. Subjects I-1, II-3, III-1, and III-2 in this family also had a history of polydipsia and polyuria. A standard water deprivation test was performed for the diagnosis of ADNDI. In subject II-3, blood AVP was 0.9 pg/ml at baseline and 2.1 pg/ml after 5 h of water intake withheld.
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FIG. 1. Family structure and haplotype analysis of ADNDI in families 1 (A) and 2 (B). Haplotype analysis indicates that the phenotype of DI cosegregates with the locus between D20S199 and D20S849 on chromosome 20 in two pedigrees, which is listed in descending order from the telomere to the centromere. Full solid symbol, Affected individual; slash mark, deceased individual; white symbol, unaffected individual; arrow, proband; square, male; circle, female; half solid symbol, individual with clinical manifestation and lack of molecular and biochemical disorders. Generations are designated by Roman numerals. STR markers are indicated by D20S117, D20S199, D20S842, D20S181, D20S889, D20S849, and D20S916. The AVP-NPII gene is located between D20S199 and D20S849.
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Informed consent was obtained from every subject participating in the study, and this study was approved by the hospital ethical board.
Water deprivation test
All water intake was withheld, and hourly measurements of blood pressure, body weight, urine volume, urine specific gravity, and urine osmolality were made until two sequential urine osmolality varied by less than 30 mOsm/kg (or less than 10%), or until 5% of body weight was lost. DDAVP (5 U) was administrated sc at the end of water deprivation. A final urine osmolality measurement was taken 60 min later. Plasma osmolality measurement was taken before the water deprivation and at the end of the test.
PCR and sequencing
PCR was performed to amplify the AVP-NPII gene in a volume of 50 µl containing 0.25 U LA-Taq (TaKaRa, Otsu, Shiga, Japan), 25 µl 2x guanosine cytidine buffer I, 0.4 mM dNTP, 100 ng genomic DNA, and 0.4 µM forward and reverse primer, respectively (Table 1). Amplification was performed by 30 cycles of denaturation at 94 C for 1min, annealing at 54–60 C for 30 sec, and extension at 72 C for 2 min. The reaction was carried out in a PTC-225 DNA Engine Tetrad (MJ Research Waltham, MA).The PCR products were purified by gel extraction kit (Omega Bio-Tek, Doraville, GA) and then were directly sequenced by ABI PRISM 3700 Genetic Analyzer (Applied Biosystems, Foster City, CA). To confirm the presence of a monoallelic mutation, subclone sequencing was performed for the exon 2 that was identified with a 3-bp deletion. The PCR products of exon 2 were ligated into T-easy vector (Promega, Madison, WI) and then transformed into Escherichia coli DH-5
cells. Positive clones were picked up and sequenced by an ABI PRISM 3700 Genetic Analyzer.
Genotyping and linkage analysis
A genomewide linkage analysis was performed using 400 microsatellite markers from 22 autosomes spaced at less than 10-cM intervals for five affected and six unaffected individuals in family 2 in which AVP-NPII mutations were not detected. The reaction was carried out in ABI PRISM Linkage Mapping Set Version 2.5 (Applied Biosystems). Furthermore, seven STR markers around AVP-NPII gene locus were chosen for fine mapping analysis including D20S117, D20S199, D20S842, D20S181, D20S889, D20S849, and D20S916. All information about microsatellite markers was obtained from the Marshfield database (http://www.marshfieldclinic.org/ research/genetics/) and the National Center for Biotechnology Information database (http://www.ncbi.nlm.nih.gov). Genomic DNA was isolated from peripheral blood leukocytes. PCR was performed according to the LI-COR Company manual using a PTC-225 DNA engine Tetrad. Multiplex PCR was carried out in a volume of 10 µl containing 50 ng genomic DNA, 2 mmol dNTP, 0.5 µM forward and reverse primers, respectively, 1 µl 10x buffer, and 0.4 U hot start Taq DNA polymerase. Denaturation was performed at 95 C for 15 min followed by 10 cycles of denaturation at 94 C for 30 sec, annealing at 55 C for 30 sec, and extension at 72 C for 2 min. The PCR products were electrophoresed on an ABI PRISMTM 3700 DNA sequencer. The sequencing data were collected and analyzed with Genescan software (version 3.7 NT) and Genotyping software (version 3.7 NT).
In linkage analysis, the disease was set as a model as autosomal dominant inheritance with complete penetrance, the affected allele frequency as 0.00001, and the marker allele frequency being uniformly distributed. The two-point linkage analysis was carried out using the MLINK program from the LINKAGE software package (version 5.2). Haplotype analysis was analyzed with CYRILLIC software (version 2.0). The allele markers were designated according to the PCR product size. 1 referred to the smallest one, 2 referred to the second smallest one, and the others were serially numbered (Fig. 1
).
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Results
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Clinical characteristics of ADNDI
All affected individuals presented with polyuria and polydipsia in both families, including nine individuals from four generations in family 1 and five individuals from three generations in family 2. The water deprivation test demonstrated the deficiencies of urine concentration in the affected individuals in two families. Urine osmolality remained below plasma osmolality after water deprivation, and urine osmolality increased by more than 50% for the affected individuals in both families after VP administration. Water intake was withheld for 3 h in family 1 and 5 h in family 2 before DDAVP administration until urine osmolality changed by less than 30 mOsm/kg by hourly measurements. Subject IV-1 from family 1 did not have the urine concentration deficiency, although he also complained of increased water intake and polyuria. The maximum urine osmolality rose to 635 mOsm/liter in response to 3 h of water deprivation, which negatively supported the diagnosis of DI (Table 2).
PCR and sequencing
Direct sequencing of PCR products showed multiple heterozygous peaks following the 1827th nucleotide of the exon 2 of AVP-NPII gene in four affected individuals of family 1, whereas the sequences of the coding area of AVP-NPII gene from those unaffected individuals and subject IV-1 were identical with that obtained from the National Center for Biotechnology Information database. Furthermore, the PCR products amplified from the affected individuals were subcloned. Subclone sequencing showed a monoallelic deletion of 3 bp (1827–1829delAGG) of exon 2, which demonstrated only one of the two alleles harboring the mutation (Fig. 2). This type of heterozygous AGG deletion was identified in all four affected subjects in family 1.
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FIG. 2. Subclone sequencing of AVP-NPII gene showed both the normal (A) and 3-bp deletion (AGG) at the position between 1827 and 1829 (B) in all the affected individuals from family 1. It is a monoallelic mutation of AVP-NPII gene in the patients with ADNDI in family 1.
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In family 2, no mutations could be detected in the coding, promoter, and intronic regions of the AVP-NPII gene by direct sequencing. Furthermore, PCR and sequencing were performed to amplify the IGR between AVP-NPII and oxytocin gene, which was reported to be the critical enhancer element for expression of these two genes in the hypothalamus in animal models. Neither deletions nor insertions were detected in the IGR. Due to an ubiquitin protein ligase activity and a possible involvement in prohormone ubiquitination, the UBCE71P5 gene as a candidate gene was also amplified and sequenced. However, no mutations could be detected in the coding regions of the UBCE7IP5 gene either.
Haplotyping and linkage analysis
In family 1, linkage was established between the gene locus and the DI phenotype according to the LOD score of 2.28 ( = 0.00) by the STR marker D20S117. All of the affected individuals (II5, II-8, III-6, and III-10) shared the same haplotype of D20S117, D20S199, and D20S849 (Fig. 1A and Table 3). In family 2, linkage could not be established between the gene locus and DI phenotype using the same STR markers as in family 1 (D20S117, D20S199, and D20S849). Fine mapping was further performed using the STR markers between D20S199 and D20S849. Favor for linkage was demonstrated with the LOD score of 1.20 ( = 0.00) by STR markers D20S842 and D20S889, which corresponded to a 7-cM interval on chromosome 20 on which the AVP-NPII gene is located (Fig. 1B and Table 3). To identify the possible corresponding locus apart from the locus between D20S199 and D20S849, the genomewide scan was performed using 400 STR markers. The corresponding locus could not be identified elsewhere on the genome except D20S889 remaining the maximum LOD score of 1.202999 ( = 0.00).
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Discussion
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In this study, we presented two ADNDI families in which the corresponding genetic deficiencies were mapped to a locus where the AVP-NPII gene is located. The DI phenotype in family 1 cosegregated with a heterozygous deletion mutation of exon 2 of the AVP-NPII gene, which was previously reported in other families (11, 12, 13). The 1827–1829delAGG mutation eliminates a glutamine at the 47th codon in the neurophysin moiety of prohormone. Glu-47 is located in the highly conserved domain of NPII and is required for AVP sorting and processing (14). In 1991, Chen et al. (15) revealed that Glu-47 was essential for neurophysin to form a salt bridge with AVP. Therefore, the deletion of Glu-47 will influence the normal structure and salt bridge formation of NPII protein. As a consequence, the aberrant precursors are not able to be folded and routed properly; finally, central DI occurs.
However, in family 2, we found no mutations in the coding region, the intronic region, and the 1.5-kb upstream region from the initial transcription site of AVP-NPII gene. The IGR between oxytocin and VP has been confirmed to be the crucial enhancer elements for the cell-specific gene expression in the hypothalamus using transgenic mouse and rat models (16). We amplified and sequenced the whole region of IGR and found no defects including deletions, insertions, and mutations. According to the linkage result, 76 genes are located in the interval between D20S199 and D20S849, but none of them appears to be directly involved in water metabolism except AVP-NPII gene. We could not exclude those corresponding genes that indirectly participate in water balance. We sequenced the UBCE7IP5 gene, which has ubiquitin protein ligase activity and is involved in protein ubiquitination (17). Its deficiency might affect the ubiquitination and degradation of AVP protein. However, we could not identify any mutations in the coding region of UBCE7IP5 gene. We also sequenced the aquaporin 2 gene (AQP2) to exclude the possibility of atypical nephrogenic DI and did not detect any mutations in all exons of AQP2. We proposed that some other corresponding gene(s) were indirectly involved in the regulation of AVP expression, production, and secretion, which might cause ADNDI in this family. To identify the corresponding locus beyond the locus between D20S199 and D20S849, we performed the genomewide haplotype analysis using 400 STR markers covering all genomes with a distance of less than 10 cM. However, the corresponding locus could not be identified on the genome except D20S889 remaining the maximum LOD score of 1.202999 ( = 0.00). Based on the genomewide scan data, we believed the corresponding gene(s) for ADNDI in family 2 was located in the 7-cM interval between D20S199 and D20S849 on chromosome 20. The possibility of haploinsufficiency due to an alteration in an enhancer should be considered, particularly given that the clinical presentations seem partial in family 2 compared with family 1, such as the mildly increased water intake and a rise of blood AVP after water deprivation.
The regulation of biosynthesis, secretion, and release of AVP is very complicated. The precursors of AVP are primarily synthesized in the large neurons of the supraoptic and paraventricular nuclei, carried by NPII packaged in granules, transported down along the axons, and stored in terminal dilatations until they are released into the systemic circulation. During the transportation, the precursors are transformed into bioactive AVP by the catalyzation of prohormone convertase 2 and polypeptide 7B2 (18). The most important regulator under physiological conditions is the effective osmotic pressure of body water. In addition, hemodynamic alterations, emetic drugs, hypoglycemia, renin-angiotensin system, stress and temperature, and hypoxia-hypercapnia also have impacts on the release of AVP. Cortisol, thyroid hormones, endothelin (19), ghrelin (20), cAMP (21), serotonin, norepinephrine (22), and NO synthase (23) can also influence the synthesis of AVP. Any abnormalities in the process of AVP-NPII will lead to deficiency of AVP secretion and central DI. To date, all the reported mutations responsible for ADNDI are located in AVP-NPII gene. However, what remains a mystery is the variation regarding the age of onset and the severity of disease observed within and between the ADNDI families. Multiple genetic factors, such as a more sensitive thirst mechanism or differential activities of the chaperone proteins that help prevent irreversible denaturation of malprocessed prohormones in the endoplasmic reticulum, may be involved in the heterogeneity (24). Therefore, other corresponding genes or enhancers located between the markers D20S199 and D20S849 on chromosome 20 might relate to the central DI in family 2.
In conclusion, the corresponding gene(s) responsible for ADNDI should not be confined to AVP-NPII gene defects. The locus between the markers D20S199 and D20S849 is possibly involved in the etiology of ADNDI in some pedigrees as in family 2 of our study. It implies a genetic diversity in the cause of ADNDI.
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Acknowledgments
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We are indebted to the two families who participated in this study. We are also grateful to Huaidong Song and Chao Xu (National Key Laboratory for Human Genome, South China Center, Shanghai, China) and Yun Lu and Heng Xu (Health Science Center, Shanghai Institute for Biological Sciences, Chinese Academy of Science, Shanghai, China) for genomewide haplotype analysis.
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Footnotes
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This work was supported by E-Institute of Shanghai Universities, Shanghai Municipal Education Commission Grant E03007.
First Published Online April 5, 2005
Abbreviations: ADNDI, Autosomal dominant neurohypophyseal DI; AVP, arginine vasopressin; DDAVP, 1-desamino-8-D-arginine vasopressin; DI, diabetes insipidus; IGR, intragenic region; STR, short tandem repeats; VP, vasopressin.
Received October 11, 2004.
Accepted March 29, 2005.
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Abstract
Introduction
