Differential Cellular Handling of Defective Arginine Vasopressin (AVP) Prohormones in Cells Expressing Mutations of the AVP Gene Associated with Autosomal Dominant and Recessive Familial Neurohypophyseal Diabetes Insipidus

An unusual mutation in the arginine vasopressin (AVP) gene, predicting a P26L amino acid substitution of the AVP prohormone, is associated with autosomal recessive familial neurohypophyseal diabetes insipidus (FNDI). To investigate whether the cellular handling of the P26L prohormone differed from that of the Y21H prohormone associated with autosomal dominant inheritance of FNDI, the mutations were examined by heterologous expression in cell lines. Immunoprecipitation demonstrated retarded processing and secretion of the Y21H prohormone, whereas the secretion of the P26L prohormone seemed to be unaffected. Confocal laser scanning microscopy showed accumulation of the Y21H prohormone in the endoplasmic reticulum, whereas the P26L prohormone and/or processed products were localized in secretory granules in the cellular processes. RIA analysis showed reduced amounts of immunoreactive Y21H-AVP and P26L-AVP in the cell culture medium. Thus, the recessive mutation does not seem to affect the intracellular trafficking but rather the final processing of the prohormone. Our results provide an important negative control in support of the hypothesis that autosomal dominant inheritance of FNDI is caused by mutations in the AVP gene that alter amino acid residues important for folding and/or dimerization of the neurophysin II moiety of the AVP prohormone and subsequent transport from the endoplasmic reticulum.

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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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“Father’s Kin”, or “Autosomal Dominant Inheritance”: Reconsidering the Opposition between Illness and Disease

Этнографическое обозрение ◽

10.31857/s086954150007773-0 ◽

2019 ◽

Keyword(s):

Autosomal Dominant ◽

Autosomal Dominant Inheritance ◽

Dominant Inheritance ◽

Illness And Disease

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Effective variant filtering and expected candidate variant yield in studies of rare human disease

npj Genomic Medicine ◽

10.1038/s41525-021-00227-3 ◽

2021 ◽

Vol 6 (1) ◽

Author(s):

Brent S. Pedersen ◽

Joe M. Brown ◽

Harriet Dashnow ◽

Amelia D. Wallace ◽

Matt Velinder ◽

...

Keyword(s):

Whole Genome Sequencing ◽

Rare Disease ◽

Genome Sequencing ◽

Autosomal Dominant ◽

De Novo ◽

Autosomal Dominant Inheritance ◽

Compound Heterozygous ◽

Whole Genome ◽

Dominant Inheritance ◽

Family Based

AbstractIn studies of families with rare disease, it is common to screen for de novo mutations, as well as recessive or dominant variants that explain the phenotype. However, the filtering strategies and software used to prioritize high-confidence variants vary from study to study. In an effort to establish recommendations for rare disease research, we explore effective guidelines for variant (SNP and INDEL) filtering and report the expected number of candidates for de novo dominant, recessive, and autosomal dominant modes of inheritance. We derived these guidelines using two large family-based cohorts that underwent whole-genome sequencing, as well as two family cohorts with whole-exome sequencing. The filters are applied to common attributes, including genotype-quality, sequencing depth, allele balance, and population allele frequency. The resulting guidelines yield ~10 candidate SNP and INDEL variants per exome, and 18 per genome for recessive and de novo dominant modes of inheritance, with substantially more candidates for autosomal dominant inheritance. For family-based, whole-genome sequencing studies, this number includes an average of three de novo, ten compound heterozygous, one autosomal recessive, four X-linked variants, and roughly 100 candidate variants following autosomal dominant inheritance. The slivar software we developed to establish and rapidly apply these filters to VCF files is available at https://github.com/brentp/slivar under an MIT license, and includes documentation and recommendations for best practices for rare disease analysis.

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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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PSEUDOGLAUCOMA OF AUTOSOMAL DOMINANT INHERITANCE

Acta Ophthalmologica ◽

10.1111/j.1755-3768.1961.tb00286.x ◽

2009 ◽

Vol 39 (4) ◽

pp. 695-695 ◽

Cited By ~ 1

Author(s):

K. Sandvig

Keyword(s):

Autosomal Dominant ◽

Autosomal Dominant Inheritance ◽

Dominant Inheritance

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Genomic features of lung cancer patients harboring germline mutations associated with hereditary cancer syndromes.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.e20511 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. e20511-e20511

Author(s):

Jian Sun ◽

Weiran Wang ◽

Danhua Wang ◽

Hongling Yuan ◽

Tonghui Ma

Keyword(s):

Lung Cancer ◽

Cancer Patients ◽

Autosomal Recessive ◽

Autosomal Dominant ◽

Autosomal Recessive Inheritance ◽

Germline Mutations ◽

Autosomal Dominant Inheritance ◽

Recessive Inheritance ◽

Dominant Inheritance ◽

Lung Cancer Patients

e20511 Background: Smoking and air pollution are the major causes of lung cancer; however, numerous studies have demonstrated that genetic factors also contribute to the development of lung cancer. Here, we reported an analysis of genomic features in 65 lung cancer patients with autosomal-dominant or autosomal-recessive inheritance of germline mutations. Methods: We retrospectively reviewed next-generation sequencing data of 26,904 lung cancer patients in a Chinese cohort. The germline mutation patterns, as well as the co-occurrence with somatic driver mutations were analyzed. Results: A total of 65 (0.24%) patients with heterozygous germline mutations associated with hereditary cancer syndromes were detected, including 27 (0.10%) patients with autosomal-dominant inheritance (BRCA1, BRCA2, RET and TP53) and 38 (0.14%) patients with autosomal-recessive inheritance (ATM, BLM, FANCA, FANCG, MUTYH, NBN, RECQL4 and WRN). Comparing to patients with autosomal-dominant inheritance (Age 56±17.8), patients with autosomal-recessive inheritance (Age 65±11.7, P = 0.009) were older, and there is no gender difference. Additionally, 66.7% (18/27) of patients with autosomal-dominant inheritance were identified co-mutated actionable variations, such as 12 patients harboring mutations in exon 18–21 of EGFR, 2 patients harboring ERBB2 exon 20 insertions, 3 patients harboring mutations in exon 2 of KRAS and 1 patient harboring EML4-ALK fusion. The coexistence of germline autosomal-dominant mutations and somatic driver mutations indicated that germline mutations have weak impact on lung cancer. Simultaneously, 52.6% (20/38) of patients with autosomal-recessive inheritance were identified co-mutated actionable variations, such as 15 EGFR+ patients, 2 ERBB2+ patients and 3 KRAS+ patients. And there was no significant difference in population frequency of co-mutated actionable variations between the two groups. Conclusions: In summary, studies on germline mutations of lung cancer patients may help to elucidate the etiology and mechanism of lung cancer, and may help for early detection and diagnosis, targeted therapy and improved prevention strategies.

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Familial Spontaneous Pneumothorax

PEDIATRICS ◽

10.1542/peds.64.2.172 ◽

1979 ◽

Vol 64 (2) ◽

pp. 172-175

Author(s):

William G. Wilson ◽

Arthur S. Aylsworth

Keyword(s):

Statistical Analysis ◽

Spontaneous Pneumothorax ◽

Autosomal Dominant ◽

Autosomal Dominant Inheritance ◽

Familial Occurrence ◽

Review Of The Literature ◽

Dominant Inheritance ◽

Pedigree Data ◽

Fathers And Sons ◽

Male To Female

A family is described in which four persons in three generations suffered spontaneous pneumothoraces: a newborn, an infant, an adolescent, and an adult. Review of the literature reveals 61 reports of familial spontaneous pneumothorax in 22 families. The ratio of male to female cases is approximately 1.8. Affected parents and affected children (including affected fathers and sons) are seen in ten families, while affected siblings with unaffected parents are noted in 13 families. Consanguinity has not been reported. Although autosomal dominant inheritance has been suggested as an explanation of familial spontaneous pneumothorax, available pedigree data are not adequate for statistical analysis. Physicians should be aware of the familial occurrence of spontaneous pneumothorax so that members of such families may be appropriately managed when problems arise.

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