scholarly journals Two Novel Mutations of the Vasopressin Gene Associated with Familial Diabetes Insipidus and Identification of an Asymptomatic Carrier Infant1

1998 ◽  
Vol 83 (11) ◽  
pp. 3958-3964
Author(s):  
Frederick D. Grant ◽  
Arshanoush Ahmadi ◽  
Catherine M. Hosley ◽  
Joseph A. Majzoub
Keyword(s):  
Diabetes Insipidus ◽  
Genomic Dna ◽  
Autosomal Dominant ◽  
Restriction Site ◽  
Asymptomatic Carrier ◽  
Dominant Mode ◽  
Heterozygous Mutation ◽  
Novel Mutations ◽  
Balance Study ◽  
Vasopressin Gene

Familial diabetes insipidus (FDI) is a syndrome of central vasopressin deficiency that is inherited in an autosomal dominant manner and that typically becomes clinically apparent in the first decade of life. Two novel mutations of the vasopressin gene have been identified in two previously unstudied kindreds with FDI. In each kindred, the inheritance of the FDI phenotype was consistent with an autosomal dominant mode of inheritance. In each proband, the diagnosis of central diabetes insipidus had been confirmed previously with a water deprivation protocol. After extraction of genomic DNA from each individual, the three exons of the vasopressin gene were separately amplified by PCR and directly sequenced using an automated dye termination method. In the proband and two other carriers of one kindred, a heterozygous C to T mutation was identified at nucleotide 1857. This is predicted to produce a serine to phenylalanine substitution at residue 56 of the vasopressin-related neurophysin peptide encoded by the mutated allele. The mutation also abolished an MspI site in the vasopressin sequence, and analysis of genomic DNA from eight members of the kindred (five with FDI) confirmed segregation of the mutation with the FDI phenotype. Another member of the kindred, a 13-month-old infant, also has the heterozygous C to T mutation, but a formal water balance study showed no evidence of diabetes insipidus. In the proband of the other kindred, a heterozygous G to A mutation was identified at nucleotide 1873. This mutation would be predicted to cause a cysteine to tyrosine substitution at residue 61 of the neurophysin encoded by the mutated allele. This heterozygous mutation was confirmed by the presence of an RsaI restriction site in one vasopressin allele in two members of the kindred. Therefore, two novel heterozygous mutations of the vasopressin gene have been identified in FDI kindreds. In one kindred, an asymptomatic carrier infant was identified and will require continued observation to determine whether she will develop clinical diabetes insipidus. The presence of these two novel mutations in a region of the vasopressin gene where other FDI mutations have been reported suggests that the part of the neurophysin peptide encoded by these sequences may be critically important in the appropriate expression of vasopressin.

scholarly journals Clinical and molecular analysis of three families with autosomal dominant neurohypophyseal diabetes insipidus associated with a novel and recurrent mutations in the vasopressin-neurophysin II gene

2002 ◽  
pp. 649-656 ◽  
Author(s):  
J Rutishauser ◽  
P Kopp ◽  
MB Gaskill ◽  
TJ Kotlar ◽  
GL Robertson
Keyword(s):  
Diabetes Insipidus ◽  
Autosomal Dominant ◽  
De Novo ◽  
Index Patient ◽  
Dominant Negative ◽  
Dominant Negative Effect ◽  
Heterozygous Mutation ◽  
Posterior Pituitary ◽  
Recurrent Mutations ◽  
Neurophysin Ii

OBJECTIVE: To test further the hypothesis that autosomal dominant neurohypophyseal diabetes insipidus (adFNDI) is caused by heterozygous mutations in the vasopressin-neurophysin II (AVP-NPII) gene that exert a dominant negative effect by producing a precursor that misfolds, accumulates and eventually destroys the neurosecretory neurons. METHODS: Antidiuretic function, magnetic resonance imaging (MRI) of the posterior pituitary and AVP-NPII gene analysis were performed in 10 affected members of three unreported families with adFNDI. RESULTS: As in previously studied patients, adFNDI apparently manifested after birth, was due to a partial or severe deficiency of AVP, and was associated with absence or diminution of the hyperintense MRI signal normally emitted by the posterior pituitary, and with a heterozygous mutation in the AVP-NPII gene. In family A, a transition 275G-->A, which predicts replacement of cysteine 92 by tyrosine (C92Y), was found in the index patient, but not in either parent, indicating that it arose de novo. The six affected members of family B had a transversion 160G-->C, which predicts replacement of glycine 54 by arginine (G54R). It appeared de novo in the oldest affected member, and was transmitted in a dominant manner. In family C, six of 15 living affected members were tested and all had a novel transition, 313T-->C, which predicts replacement of cysteine 105 by arginine (C105R). It, too, was transmitted in a dominant manner. As in other patients with adFNDI, the amino acids replaced by the mutations in these three families are known to be particularly important for correct and efficient folding of the precursor. CONCLUSIONS: These findings are consistent with the malfolding/toxicity hypothesis underlying the pathogenesis of adFNDI. Moreover, they illustrate the value of genetic analysis in all patients who develop idiopathic diabetes insipidus in childhood, even if no other family members are affected.

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

2008 ◽  
Vol 52 (8) ◽  
pp. 1272-1276 ◽  
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.

scholarly journals A mutated CRYGD associated with congenital coralliform cataracts in two Chinese pedigrees

2021 ◽  
Vol 14 (6) ◽  
pp. 800-804
Author(s):  
Su-Ping Cai ◽  
◽  
Xi-Zhen Wang ◽  
Yun Wang ◽  
Fen He ◽  
...  
Keyword(s):  
Congenital Cataract ◽  
Autosomal Dominant ◽  
Family Members ◽  
Dominant Mode ◽  
Heterozygous Mutation ◽  
Sequencing Analysis ◽  
Causal Gene ◽  
Exon 2 ◽  
Coding Regions ◽  
Coralliform Cataract

AIM: To investigate the causal gene mutation and clinical characteristics for two Chinese families with autosomal dominant congenital coralliform cataract. METHODS: Two Chinese pedigrees with congenital cataract were investigated. Routine ophthalmic examinations were performed on all patients and non-affected family members. Peripheral blood samples were collected, and the genomic DNAs were extracted. The coding regions of proband’s DNAs were analyzed with cataract gene panel. The identified mutation was amplified by polymerase chain reaction, and automated sequencing was performed in other members of two families to verify whether the mutated gene was co-segregated with the disease. RESULTS: Congenital coralliform cataract was inherited in an autosomal dominant mode in both pedigrees. For each family, more than half of the family members were affected. All patients presented with severe visual impairment after birth as a result of bilateral symmetric coralliform lens opacification. An exact the same defect in the same gene, a heterozygous mutation of c.70C>A (p. P24T) in exon 2 of γD-crystallin gene, was detected in both probands from each family. Sanger sequencing analysis demonstrated that the mutated CRYGD was co-segregated in these two families. CONCLUSION: A c.70C>A (p. P24T) variant in CRYGD gene was reconfirmed to be the causal gene in two Chinese pedigrees. It is known that mutated CRYGD caused most of the congenital coralliform cataracts, suggesting that the CRYGD gene is associated with coralliform congenital cataract.

Forty-One Individuals With Mutations in the AVP-NPII Gene Associated With Familial Neurohypophyseal Diabetes Insipidus

2020 ◽  
Vol 105 (4) ◽  
pp. 1112-1118 ◽  
Author(s):  
Alejandro García-Castaño ◽  
Leire Madariaga ◽  
Gustavo Pérez de Nanclares ◽  
Amaia Vela ◽  
Itxaso Rica ◽  
...  
Keyword(s):  
Quality Control ◽  
Diabetes Insipidus ◽  
Sanger Sequencing ◽  
Autosomal Dominant ◽  
Genetic Characterization ◽  
Pathogenic Variants ◽  
Vasopressin Gene ◽  
Neurophysin Ii ◽  
Gene Alterations

Abstract Context Familial neurohypophyseal diabetes insipidus is a rare disease produced by a deficiency in the secretion of antidiuretic hormone and is caused by mutations in the arginine vasopressin gene. Objective Clinical, biochemical, and genetic characterization of a group of patients clinically diagnosed with familial neurohypophyseal diabetes insipidus, 1 of the largest cohorts of patients with protein neurophysin II (AVP-NPII) gene alterations studied so far. Design The AVP-NPII gene was screened for mutations by PCR followed by direct Sanger sequencing in 15 different unrelated families from Spain. Results The 15 probands presented with polyuria and polydipsia as the most important symptoms at the time of diagnosis. In these patients, the disease was diagnosed at a median of 6 years of age. We observed 11 likely pathogenic variants. Importantly, 4 of the AVP-NPII variants were novel (p.(Tyr21Cys), p.(Gly45Ser), p.(Cys75Tyr), p.(Gly88Cys)). Conclusions Cytotoxicity seems to be due to consequences common to all the variants found in our cohort, which are not able to fold correctly and pass the quality control of the ER. In concordance, we found autosomal dominant familial neurohypophyseal diabetes insipidus in the 15 families studied.

scholarly journals R116C mutation in PRSS1 gene causes hereditary pancreatitis and elevated creatine kinase in one child：a case report

2021 ◽  
Author(s):  
Yong Wei Cheng ◽  
Shao Ming Zhou ◽  
Dong Ling Dai
Keyword(s):  
Acute Pancreatitis ◽  
Creatine Kinase ◽  
Genomic Dna ◽  
Autosomal Dominant ◽  
Heterozygous Mutation ◽  
Hereditary Pancreatitis ◽  
Recurrent Acute Pancreatitis ◽  
Case Presentation ◽  
Elevated Creatine Kinase ◽  
Exon Gene

Abstract Background Functionally acquired mutations in the PRSS1 gene can lead to autosomal dominant hereditary pancreatitis (Hereditary Pancreatitis, HP). The most frequently reported mutation sites are R122H, N29I, A16V, and R122C. R116C mutation was less frequently reported to be associated with HP. Moreover, there are few reports about association of hereditary pancreatitis with elevated creatine kinase in children. Case presentation: We reported a patient presented with repeated abdominal pain and recurrent acute pancreatitis accompanied by elevated creatine kinase. The genomic DNA of lymphocytes from peripheral blood was extracted for whole exon gene analysis. The patient had a heterozygous mutation in exon 3 c.346C > T, resulting in substitution of cysteine at position 116 with arginine (p.R116C). Her father had the same mutation in exon 3 c.346C > T. The diagnosis of hereditary pancreatitis due to R116C mutation in PRSS1 gene was confirmed. Conclusions The patient's hereditary pancreatitis is caused by the mutation of PRSS1 gene R116C, characterized by elevated creatine kinase in patient.

scholarly journals A Novel Mutation in COL4A1 Gene in a Chinese Family with Pontine Autosomal Dominant Microangiopathy and Leukoencephalopathy

2021 ◽  
Author(s):  
Qing Li ◽  
Chengfeng Wang ◽  
Wei Li ◽  
Zaiqiang Zhang ◽  
Shanshan Wang ◽  
...  
Keyword(s):  
Basement Membrane ◽  
Skin Biopsy ◽  
Exome Sequencing ◽  
Whole Exome Sequencing ◽  
Autosomal Dominant ◽  
Chinese Family ◽  
Heterozygous Mutation ◽  
Collagen Type Iv ◽  
Lacunar Infarcts ◽  
Whole Exome

AbstractPontine autosomal dominant microangiopathy and leukoencephalopathy (PADMAL) is a rare hereditary cerebral small vessel disease. We report a novel collagen type IV alpha 1 (COL4A1) gene mutation in a Chinese family with PADMAL. The index case was followed up for 6 years. Neuroimaging, whole-exome sequencing, skin biopsy, and pedigree analysis were performed. She initially presented with minor head injury at age 38. MRI brain showed chronic lacunar infarcts in the pons, left thalamus, and right centrum semiovale. Extensive workup was unremarkable except for a patent foramen ovale (PFO). Despite anticoagulation, PFO closure, and antiplatelet therapy, the patient had recurrent lacunar infarcts in the pons and deep white matter, as well as subcortical microhemorrhages. Whole-exome sequencing demonstrated a novel c.*34G > T mutation in the 3′ untranslated region of COL4A1 gene. Skin biopsy subsequently demonstrated thickening of vascular basement membrane, proliferation of endothelial cells, and stenosis of vascular lumen. Three additional family members had gene testing and 2 of them were found to have the same heterozygous mutation. Of the 18 individuals in the pedigree of 3 generations, 12 had clinical and MRI evidence of PADMAL. The mechanisms of both ischemic and hemorrhagic stroke are likely the overexpression of COLT4A1 in the basement membrane and frugality of the vessel walls. Our findings suggest that the novel c.*34G > T mutation appears to have the same functional consequences as the previously reported COL4A1 gene mutations in patients with PADMAL and multi-infarct dementia of Swedish type.

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