A novel AVP gene mutation in a Turkish family with neurohypophyseal diabetes insipidus

AbstractFamilial neurohypophyseal diabetes insipidus (FNDI) is an autosomal dominant hereditary disorder characterized by severe polydipsia and polyuria that usually presents in early childhood. In this study, we describe a new arginine vasopressin (AVP) gene mutation in an ethnic German family with FNDI and provide an overview of disease-associated AVP-gene mutations that are already described in literature. Three members of a German family with neurohypophyseal diabetes insipidus were studied. Isolated DNA from peripheral blood samples was used for mutation analysis by sequencing the whole coding region of AVP-NPII gene. Furthermore, we searched the electronic databases MEDLINE (Pubmed) as well as HGMD, LOVD-ClinVar, db-SNP and genomAD in order to compare our cases to that of other patients with FNDI. Genetic analysis of the patients revealed a novel heterozygote missense mutation in exon 2 of the AVP gene (c.274T>G), which has not yet been described in literature. We identified reports of more than 90 disease-associated mutations in the AVP gene in literature. The novel mutation of the AVP gene seems to cause FNDI in the presented German family. Similar to our newly detected mutation, most mutations causing FNDI are found in exon 2 of the AVP gene coding for neurophysin II. Clinically, it is important to think of FNDI in young children presenting with polydipsia and polyuria.

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Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a novel missense mutation in AVP gene in a large Italian kindred

Endocrine ◽

10.1007/s12020-021-02830-x ◽

2021 ◽

Author(s):

Carlotta Marzocchi ◽

Silvia Cantara ◽

Alfonso Sagnella ◽

Maria Grazia Castagna ◽

Marco Capezzone

Keyword(s):

Diabetes Insipidus ◽

Missense Mutation ◽

Autosomal Dominant ◽

Three Dimensional ◽

Rare Condition ◽

Central Diabetes Insipidus ◽

Disulfide Bridges ◽

Italian Family ◽

Avp Gene

Abstract Purpose Familial neurohypophysial diabetes insipidus (FNDI), commonly caused by autosomal dominant arginine vasopressin (AVP) mutations, is a rare condition in which vasopressin fails in regulating body’s level of water with final polyuria and polydipsia. Genetic testing in familial cases of FNDI should be carry out to ensure adequate treatments and avoid disease manifestations especially in infants. Methods In this study, we investigated three-generations of a large Italian family with clinical diagnosis of familial central diabetes insipidus for the presence of potential pathogenic mutations in the AVP gene. Results We identified a heterozygous missense mutation (c.154 T > A; p.C52S) in AVP gene in all affected members studied of a large Italian family. In silico tools were used to investigate the pathogenic role of the mutation and three-dimensional protein structure predicted that the p.C52S impairs disulfide bridges formation resulting in misfolding of the protein. Conclusions This is the first study that identified a novel missense p.C52S mutation as causative of central diabetes insipidus in a large Italian pedigree.

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Mild Congenital Primary Hypothyroidism in a Turkish Family Caused by a Homozygous Missense Thyrotropin Receptor (TSHR) Gene Mutation (A593 V)

Experimental and Clinical Endocrinology & Diabetes ◽

10.1055/s-2005-865914 ◽

2005 ◽

Vol 113 (10) ◽

pp. 582-585 ◽

Cited By ~ 8

Author(s):

S. Fricke-Otto ◽

N. Pfarr ◽

R. Mühlenberg ◽

J. Pohlenz

Keyword(s):

Gene Mutation ◽

Primary Hypothyroidism ◽

Thyrotropin Receptor ◽

Turkish Family ◽

Tshr Gene

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Characterization of an Aquaporin-2 Water Channel Gene Mutation Causing Partial Nephrogenic Diabetes Insipidus in a Mexican Family: Evidence of Increased Frequency of the Mutation in the Town of Origin

Journal of the American Society of Nephrology ◽

10.1097/01.asn.0000125248.85135.43 ◽

2004 ◽

Vol 15 (5) ◽

pp. 1223-1231 ◽

Cited By ~ 22

Author(s):

C. Boccalandro

Keyword(s):

Diabetes Insipidus ◽

Gene Mutation ◽

Nephrogenic Diabetes Insipidus ◽

Water Channel ◽

Channel Gene ◽

Aquaporin 2 ◽

Mexican Family ◽

The Town

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Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a novel mutation in arginine-vasopressin gene in a Brazilian family

Arquivos Brasileiros de Endocrinologia & Metabologia ◽

10.1590/s0004-27302008000800011 ◽

2008 ◽

Vol 52 (8) ◽

pp. 1272-1276 ◽

Cited By ~ 4

Author(s):

Maria Edna de Melo ◽

Suemi Marui ◽

Vinícius Nahime de Brito ◽

Marcio Corrêa Mancini ◽

Berenice B. Mendonca ◽

...

Keyword(s):

Diabetes Insipidus ◽

Arginine Vasopressin ◽

Autosomal Dominant ◽

Novel Mutation ◽

Direct Sequencing ◽

Sequencing Analysis ◽

The Novel ◽

Autosomal Dominant Disorder ◽

Vasopressin Gene ◽

Avp Gene

Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is a rare autosomal dominant disorder characterized by polyuria and polydipsia due to deficiency of arginine vasopressin (AVP). More than 50 mutations causing adFNDI have been already reported in the AVP gene. The aim of the present study is to analyze the AVP gene in four generations of one Brazilian kindred with adFNDI. The proband was a 31-year old female with huge hypotonic polyuria (10 L/day) dated from childhood. Molecular analysis included amplification of all exons and exon-intron regions of the AVP gene by PCR and direct sequencing. Sequencing analysis showed a novel point mutation in heterozygous: G88V (GGC>GTC). All affected patients presented the same mutation also in heterozygous, while it was absent in four normal members. We expand the repertoire of mutations in AVP describing the novel G88V mutation in one Brazilian kindred with adFNDI.

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A Novel Synonymous Variant in the AVP Gene Associated with Autosomal Dominant Familial Neurohypophyseal Diabetes Insipidus Causes Partial RNA Missplicing

Neuroendocrinology ◽

10.1159/000491579 ◽

2018 ◽

Vol 107 (2) ◽

pp. 167-180

Author(s):

Helene Kvistgaard ◽

Jane H. Christensen ◽

Jan-Ove Johansson ◽

Niels Gregersen ◽

Charlotte Siggaard Rittig ◽

...

Keyword(s):

Diabetes Insipidus ◽

Laser Scanning ◽

Dna Analysis ◽

Autosomal Dominant ◽

Challenge Test ◽

Family Members ◽

Laser Scanning Microscopy ◽

Confocal Laser ◽

Synonymous Variant ◽

Avp Gene

Objective: Autosomal dominant familial neurohypophyseal diabetes insipidus (adFNDI) is characterized by severe polyuria and polydipsia and is caused by variations in the gene encoding the AVP prohormone. This study aimed to ascertain a correct diagnosis, to identify the underlying genetic cause of adFNDI in a Swedish family, and to test the hypothesis that the identified synonymous exonic variant in the AVP gene (c.324G>A) causes missplicing and endoplasmic reticulum (ER) retention of the prohormone. Design/Patients: Three affected family members were admitted for fluid deprivation test and dDAVP (1-deamino-8-d-arginine-vasopressin) challenge test. Direct sequencing of the AVP gene was performed in the affected subjects, and genotyping of the identified variant was performed in family members. The variant was examined by expression of AVP minigenes containing the entire coding regions as well as intron 2 of AVP. Methods/Results: Clinical tests revealed significant phenotypical variation with both complete and partial adFNDI phenotype. DNA analysis revealed a synonymous c.324G>A substitution in one allele of the AVP gene in affected family members only. Cellular studies revealed both normally spliced and misspliced pre-mRNA in cells transfected with the AVP c.324G>A minigene. Confocal laser scanning microscopy showed collective localization of the variant prohormone to ER and vesicular structures at the tip of cellular processes. Conclusion: We identified a synonymous variant affecting the second nucleotide of exon 3 in the AVP gene (c.324G>A) in a family in which adFNDI segregates. Notably, we showed that this variant causes partial missplicing of pre-mRNA, resulting in accumulation of the variant prohormone in ER. Our study suggests that even a small amount of aberrant mRNA might be sufficient to disturb cellular function, resulting in adFNDI.

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