Annals of Clinical & Laboratory Science 38:12-14 (2008)
© 2008 Association of Clinical Scientists
Mutation of Glu78 of the AVP-NPII Gene Impairs Neurophysin as a Carrier Protein for Arginine Vasopressin in a Family with Neurohypophyseal Diabetes Insipidus
Yong-Wha Lee1,*,
Kyung Wook Lee2,*,
Ji Won Ryu2,
Ji Oh Mok2,
Chang-Seok Ki3,
Hyeong Kyu Park2,
Yeo Joo Kim2,
Sang Jin Kim2,
Dong Won Byun2,
Kyo Ill Suh2,
Myung Hi Yoo2,
Hee Bong Shin1,
You Kyoung Lee1 and
Chul-Hee Kim2
1 Department of Laboratory Medicine, Bucheon Hospital and Soonchunhyang University College of Medicine, Bucheon; 2 Department of Internal Medicine, Soonchunhyang University College of Medicine, Bucheon; and 3 Department of Laboratory Medicine, Samsung Medical Center, Sungkyunkwan University School of Medicine, Seoul, Korea
Address correspondence to Chul-Hee Kim, M.D., Department of Internal Medicine, Soonchunhyang University, Bucheon Hospital, Bucheon 420-767, South Korea; tel 82 32 621 5155; fax 82 32 621 5018; e-mail chkimem{at}schbc.ac.kr.
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Abstract
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Familial neurohypophyseal diabetes insipidus (FNDI; OMIM 192340
[OMIM]
) is a rare inherited disorder with an autosomal dominant inheritance pattern. It is characterized by persistent polydipsia and polyuria induced by deficient or absent secretion of arginine vasopressin (AVP). We report a Korean kindred in whom FNDI is associated with a novel deletion mutation in exon 2 of the AVP-NPII gene encoding the neurophysin II moiety. An 18-yr-old man with polyuria and polydipsia was shown to have central diabetes insipidus by using the water deprivation test. Four family members were suspected to have symptomatic vasopressin-deficient diabetes insipidus. Direct sequencing of the AVP-NPII gene showed a heterozygous GAG deletion mutation in exon 2, which results in in-frame deletion of glutamic acid (c.232_234delGAG; p.Glu78del). The mutation was predicted to yield an abnormal AVP precursor lacking Glu78 (E78) in its neurophysin II moiety. Because Glu78 is essential for neurophysin II molecules to form a salt bridge with AVP, the function of neurophysin as a carrier protein for AVP would be impaired. The proband’s mother and sister have the same mutation. Presence of this mutation suggests that the portion of the neurophysin peptide encoded by this sequence is important for the appropriate expression of vasopressin.
Keywords: diabetes insipidus, AVP-NPII gene, neurophysin, arginine vasopressin
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Introduction
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Familial neurohypophyseal diabetes insipidus (FNDI; OMIM 192340
[OMIM]
) is a rare inherited disorder with an autosomal dominant inheritance pattern. It is characterized by persistent polydipsia and polyuria induced by deficient or absent secretion of arginine vasopressin (AVP). The 2.5 kb AVP-NPII gene is located on chromosome 20p13 and consists of 3 exons [1]. Since the first report of a mutation in this gene [2], 53 different mutations have been identified (Human Gene Mutation Database, Institute of Medical Genetics, Cardiff, Wales, UK). Among the AVP-NPII mutations related to FNDI, deletion mutations have been reported in only 4 cases [3–6]. We report a Korean family with FNDI in whom we identified a novel in-frame deletion mutation (c.232_234delGAG; p.Glu78del) in the AVP-NPII gene.
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Materials and Methods
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The proband was an 18-yr-old man admitted to our hospital because of a long-lasting history of polyuria and polydipsia. His mother, sister, uncle, and cousin reported having the same symptoms for a long period of time (Fig. 1
). The patient underwent a water deprivation test. The patient’s mother, sister, uncle, and cousin refused to undergo this test.
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Fig. 1. Pedigree of the family with FNDI. The proband (III-3) is marked by an arrow. Genetically tested individuals are indicated by the "+" symbol.
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After we had obtained informed consent, blood samples were collected from the proband and his family members for genetic analysis. Genomic DNA was isolated from peripheral blood leukocytes using a Wizard genomic DNA purification kit (Promega, Madison, WI, USA), following the manufacturer’s instructions. All 3 coding exons of the AVP-NPII gene were PCR-amplified using primers designed by the authors (primer sets available upon request). After treatment of the amplicon (5 µl) with 10 U shrimp alkaline phosphatase and 2 U exonuclease I (USB Corp., Cleveland, OH, USA), sequencing was done with the BigDye terminator cycle sequencing ready reaction kit (Applied Biosystems, Foster City, CA, USA) and ABI Prism 3100 genetic analyzer (Applied Biosystems). All novel mutations were confirmed by sequencing 100 control chromosomes.
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Results
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The water deprivation test of the index patient, shown in Table 1, confirmed the presence of complete AVP-responsive diabetes insipidus. The basal plasma AVP level was 2.4 pg/ml. Plasma levels of PRL, GH, IGF-1, FSH, LH, ACTH, cortisol, TSH, free T4, and T3 were within the normal ranges. MRI of the pituitary showed a normal neurohypophysis and pituitary stalk. The patient was started on desmopressin treatment, after which his polyuria and polydipsia were satisfactorily controlled.
Direct sequencing analysis of the AVP-NPII gene in the proband revealed a heterozygous GAG deletion mutation in exon 2, which results in an in-frame deletion of glutamic acid (c.232_234delGAG; p.Glu78del). The AVP-NPII genes of the patient’s mother and sister were found to have the same mutation (Fig. 2).
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Fig. 2. Mutation analysis of the proband’s AVP gene. Direct sequencing of exon 2 shows overlapped peaks (arrow) from the nucleotide position 232 due to a heterozygous GAG deletion, which results in an in-frame deletion of a glutamic acid residue (c.232_234delGAG; p.Glu78del). The proband’s mother and sister have the same mutation as the proband.
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Discussion
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We report a novel mutation of the AVP-NPII gene that is associated with FNDI in a Korean family. In the first Korean kindred with FNDI, Tae et al [7] reported a family with a deletion mutation of a single nucleotide within the splice acceptor site of intron 2 (IVS2+1 delG). The mutation in the pedigree identified here consisted of a 3-bp deletion (GAG) affecting 2 consecutive sequences (nucleotides 232–234) in exon 2. The mutation was predicted to yield an abnormal AVP precursor lacking Glu78 (E78) in its neurophysin II moiety. Because Glu78 is essential for neurophysin II molecules to form a salt bridge with AVP, the function of neurophysin as a carrier protein for AVP would be impaired [6]. As a result, AVP most likely undergoes accelerated proteolytic degradation [6]. Interestingly, at the same locus the transition A233G, causing substitution of Glu78Gly, was previously reported in a family with FNDI [8]. The mutation in our patient’s family is quite different and unusual, however, because the deletion of Glu78 is followed by a frameshift that affects only the following codon but not the remainder of the reading frame, which is entirely preserved.
Although the other family members were not evaluated for diabetes insipidus, autosomal dominant transmission of the disease is indicated by the fact that the proband’s sister, mother, uncle, and cousin each has a long history of polyuria and polydipsia. Also, the proband’s grandfather might have been the first person in the family to be affected, and thus would be expected to have milder signs, although he was not tested.
In summary, we detected a deletion mutation in the AVP-NPII gene of a Korean kindred with FNDI. While not directly clarifying the mechanism underlying development of FNDI, this novel mutation provides a basis for understanding the characteristics of neurophysin II that cause precursor misprocessing.
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Footnotes
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* These authors contributed equally to this study. 
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References
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- Baylis PH, Robertson GL. Vasopressin function in familial cranial diabetes insipidus. Postgrad Med J 1981;57:36–40.[Abstract/Free Full Text]
- Ito M, Mori Y, Oiso Y, Saito H. A single base substitution in the coding region for neurophysin II associated with familial central diabetes insipidus. J Clin Invest 1991;87: 725–728.[Medline]
- Fluck CE, Deladoey J, Nayak S, Zeller O, Kopp P, Mullis PE. Autosomal dominant neurohypophyseal diabetes insipidus in a Swiss family, caused by a novel mutation (C59Delta/A60W) in the neurophysin moiety of preprovasopressin-neurophysin II (AVP-NP II). Eur J Endocrinol 2001;144:439–444.
- Rutishauser J, Boni-Schnetzler M, Boni J, Wichmann W, Huisman T, Vallotton MB, Froesch ER. A novel point mutation in the translation initiation codon of the pre-pro-vasopressin-neurophysin II gene: cosegregation with morphological abnormalities and clinical symptoms in autosomal domionant neurophyseal diabetes insipidus. J Clin Endocrinol Metab 1996;81:192–198.[Abstract]
- Wahlstrom JT, Fowler MJ, Nicholson WE, Kovacs WJ. A novel mutation in the preprovasopressin gene identified in a kindred with autosomal dominant neurohypophyseal diabetes insipidus. J Clin Endocrinol Metab 2004;89: 1963–1968.[Abstract/Free Full Text]
- Yuasa H, Ito M, Nagasaki H, Oiso Y, Miyamoto S, Sasaki N, Saito H. Glu-47, which forms a salt bridge between neurophysin-II and arginine vasopressin, is deleted in patients with familial central diabetes insipidus. J Clin Endocrinol Metab 1993;77:600–604.[Abstract]
- Tae HJ, Baek KH, Shim SM, Yoo SJ, Kang MI, Cha BY, Lee KW, Son HY, Kang SK. A novel splice site mutation of the arginine vasopressin-neurophysin II gene identified in a kindred with autosomal dominant familial neurohypophyseal diabetes insipidus. Mol Genet Metab 2005; 86:307–313.[Medline]
- Rittig S, Robertson GI, Siggaard C, Kovacs L, Gregersen N, Nyborg J, Pedersen EB. Identification of 13 new mutations in the vasopressin-neurophysin II gene in 17 kindreds with familial autosomal dominant neurohypophyseal diabetes insipidus. Am J Hum Genet 1996;58: 107–117.[Medline]
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Abstract
Introduction
