Unusual Segregation of APP Mutations in Monogenic Alzheimer Disease

APP gene mutations causing Alzheimer disease (AD) segregate in an autosomal dominant pattern. We report on a 40-year-old woman with a severe cognitive decline starting at 36 years, while her affected relatives presented symptoms onset in the 6th decade. The proband carried an APP missense variant in homozygous state (NM_000484.4: c.2032G>A; NP_000475.1: p.Asp678Asn; rs63750064) and showed a more severe clinical picture than the other AD relatives, as regards the age of onset and the rate of disease progression. This mutation behaves as a semi-dominant trait. The very rare chance of studying APP mutations in the homozygous state demonstrates they are not always dominant and other segregation models are possible.

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Otological lesions in pachyonychia congenita syndrome

The Journal of Laryngology & Otology ◽

10.1017/s0022215100135972 ◽

1996 ◽

Vol 110 (12) ◽

pp. 1145-1147

Author(s):

Ricardo Ferreira Bento ◽

Maria Heleba Guatimosim ◽

Rogério de Leão Bensadon ◽

Tanit Ganz Sanchez ◽

Richard Louis Voegels

Keyword(s):

Autosomal Dominant ◽

Signs And Symptoms ◽

The Other ◽

Dominant Trait ◽

Autosomal Dominant Trait ◽

Pachyonychia Congenita

AbstractThe authores report a case of patient with pachyonychia syndrome, a rare genedermatosis inherited as an autosomal dominant trait, who also had otological lesions beyond the other classic signs and symptoms of the syndrome. Many kinds of treatment have already been proposed, but all failed to show satisfactory results. A new, cheap and easy-to-use treatment was developed in this study, using keratoplastics interpolated with humectant lotion for 90 days. The results after three years of follow-up are still thoroughly satisfactory.

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Branchio-oto-renal syndrome

10.1093/med/9780199592548.003.0358 ◽

2015 ◽

Author(s):

Udo Vester ◽

Stefanie Weber

Keyword(s):

Autosomal Dominant ◽

Clinical Symptoms ◽

Renal Involvement ◽

Gene Mutations ◽

Branchial Arch ◽

Dominant Trait ◽

Autosomal Dominant Trait ◽

Bor Syndrome ◽

Ear Malformations ◽

Ear Anomalies

Branchio-oto-renal (BOR) syndrome involves branchial arch fistulas or cysts, ear malformations with hearing loss, and anomalies of the kidney. BOR syndrome is inherited in an autosomal dominant trait and is caused in most cases by mutations in the EYA1 gene. A few families with gene mutations in SIX1 or SIX5 have also been described. The variability of clinical symptoms is wide. Renal involvement is observed in the majority of cases ranging from mild anomalies (e.g. dilation or duplication of the urinary tract) to severe hypodysplasia of the kidneys which eventually lead to renal failure. Branchio-otic syndrome (BOS) is characterized by branchial arch and ear anomalies without detectable renal pathology. BOR and BOS can be seen within the same family.

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Protective mutation A673T as a potential gene therapy for most forms of APP Familial Alzheimer’s Disease

10.1101/2020.07.22.215616 ◽

2020 ◽

Author(s):

Antoine Guyon ◽

Joël Rousseau ◽

Gabriel Lamothe ◽

Jacques P. Tremblay

Keyword(s):

Alzheimer’S Disease ◽

Alzheimer's Disease ◽

Gene Therapy ◽

Alzheimer Disease ◽

Gene Mutations ◽

Aβ Peptide ◽

Aβ Peptides ◽

Familial Alzheimer Disease ◽

App Gene ◽

The Brain

AbstractThe accumulation of plaque in the brain leads to the onset and development of Alzheimer’s disease. The Amyloid precursor protein (APP) is usually cut by α-secretase, however an abnormal cleavage profile by β-secretase (BACE1) leads to the accumulation of Aβ peptides, which forms these plaques. Numerous APP gene mutations favor plaque accumulation, causing Familial Alzheimer Disease (FAD). However, a variant of the APP gene (A673T) in Icelanders reduces BACE1 cleavage by 40 %. A library of plasmids containing APP genes with 29 FAD mutations with or without the additional A673T mutation was generated and transfected in neuroblastomas to assess the effect of this mutation on Aβ peptide production. In most cases the production of Aβ peptides was decreased by the co-dominant A673T mutation. The reduction of Aβ peptide concentrations for the London mutation (V717I) even reached the same level as A673T carriers. These results suggest that the insertion of A673T in the APP gene of genetically susceptible FAD patients may prevent the onset of, slow down, or stop the progression of the disease.

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Autosomal Dominant Neurohypophyseal Diabetes Insipidus with Linkage to Chromosome 20p13 but without Mutations in the AVP-NPII Gene

The Journal of Clinical Endocrinology & Metabolism ◽

10.1210/jc.2004-2000 ◽

2005 ◽

Vol 90 (7) ◽

pp. 4388-4393 ◽

Cited By ~ 18

Author(s):

Lei Ye ◽

Xiaoying Li ◽

Ying Chen ◽

Hongtao Sun ◽

Weiqing Wang ◽

...

Keyword(s):

Diabetes Insipidus ◽

Water Deprivation ◽

Autosomal Dominant ◽

Gene Mutations ◽

Dominant Trait ◽

Lod Score ◽

Autosomal Dominant Trait ◽

Enhancer Element ◽

Vasopressin Precursor ◽

Chromosome 20P13

Abstract 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 (θ = 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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Faculty Opinions recommendation of APP locus duplication causes autosomal dominant early-onset Alzheimer disease with cerebral amyloid angiopathy.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.4119.496314 ◽

2006 ◽

Author(s):

Florence Thibaut

Keyword(s):

Alzheimer Disease ◽

Cerebral Amyloid Angiopathy ◽

Early Onset ◽

Autosomal Dominant ◽

Amyloid Angiopathy ◽

Cerebral Amyloid

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Expanding the genetic spectrum of primary familial brain calcification due to SLC2OA2 mutations: a case series

Neurogenetics ◽

10.1007/s10048-021-00634-9 ◽

2021 ◽

Author(s):

Luca Magistrelli ◽

Roberta Croce ◽

Fabiola De Marchi ◽

Chiara Basagni ◽

Miryam Carecchio ◽

...

Keyword(s):

Autosomal Dominant ◽

Case Series ◽

Dominant Trait ◽

Autosomal Dominant Trait ◽

Phenotypic Spectrum ◽

Primary Familial Brain Calcification ◽

Psychiatric Disturbances ◽

Brain Calcification ◽

Uncertain Significance ◽

Six Genes

AbstractPrimary familial brain calcification (PFBC) is a neurological condition characterized by the presence of intracranial calcifications, mainly involving basal ganglia, thalamus, and dentate nuclei. So far, six genes have been linked to this condition: SLC20A2, PDGFRB, PDGFB, and XPR1 inherited as autosomal-dominant trait, while MYORG and JAM2 present a recessive pattern of inheritance. Patients mainly present with movement disorders, psychiatric disturbances, and cognitive decline or are completely asymptomatic and calcifications may represent an occasional finding. Here we present three variants in SLC20A2, two exonic and one intronic, which we found in patients with PFBC associated to three different clinical phenotypes. One variant is novel and two were already described as variants of uncertain significance. We confirm the pathogenicity of these three variants and suggest a broadening of the phenotypic spectrum associated with mutations in SLC20A2.

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A Case Report of a Prenatally Missed Mowat-Wilson Syndrome With Isolated Corpus Callosum Agenesis

Child Neurology Open ◽

10.1177/2329048x211006511 ◽

2021 ◽

Vol 8 ◽

pp. 2329048X2110065

Author(s):

Nesrin Şenbil ◽

Zeynep Arslan ◽

Derya Beyza Sayın Kocakap ◽

Yasemin Bilgili

Keyword(s):

Corpus Callosum ◽

Autosomal Dominant ◽

Genetic Disorder ◽

Gene Mutations ◽

Hirschsprung Disease ◽

Agenesis Of Corpus Callosum ◽

Whole Exome ◽

Congenital Cardiac Anomalies ◽

History Of ◽

Gene Mutation Analysis

Mowat–Wilson syndrome (MWS) is an autosomal dominant genetic disorder caused by ZEB2 gene mutations, manifesting with unique facial characteristics, moderate to severe intellectual problems, and congenital malformations as Hirschsprung disease, genital and ophthalmological anomalies, and congenital cardiac anomalies. Herein, a case of 1-year-old boy with isolated agenesis of corpus callosum (IACC) in the prenatal period is presented. He was admitted postnatally with Hirschsprung disease (HSCR), hypertelorism, uplifted earlobes, deeply set eyes, frontal bossing, oval-shaped nasal tip, ‘‘M’’ shaped upper lip, opened mouth and prominent chin, and developmental delay. Hence, MWS was primarily considered and confirmed by the ZEB2 gene mutation analysis. His karyotype was normal. He had a history of having a prenatally terminated brother with similar features. Antenatally detected IACC should prompt a detailed investigation including karyotype and microarray; even if they are normal then whole exome sequencing (WES) should be done.

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Mirtron-mediated RNA knockdown/replacement therapy for the treatment of dominant retinitis pigmentosa

Nature Communications ◽

10.1038/s41467-021-25204-3 ◽

2021 ◽

Vol 12 (1) ◽

Author(s):

Harry O. Orlans ◽

Michelle E. McClements ◽

Alun R. Barnard ◽

Cristina Martinez-Fernandez de la Camara ◽

Robert E. MacLaren

Keyword(s):

Retinitis Pigmentosa ◽

Autosomal Dominant ◽

Gene Mutations ◽

Adeno Associated Virus ◽

Treatment Development ◽

Common Cause ◽

Toxic Protein ◽

Rna Knockdown

AbstractRhodopsin (RHO) gene mutations are a common cause of autosomal dominant retinitis pigmentosa (ADRP). The need to suppress toxic protein expression together with mutational heterogeneity pose challenges for treatment development. Mirtrons are atypical RNA interference effectors that are spliced from transcripts as short introns. Here, we develop a novel mirtron-based knockdown/replacement gene therapy for the mutation-independent treatment of RHO-related ADRP, and demonstrate efficacy in a relevant mammalian model. Splicing and potency of rhodopsin-targeting candidate mirtrons are initially determined, and a mirtron-resistant codon-modified version of the rhodopsin coding sequence is validated in vitro. These elements are then combined within a single adeno-associated virus (AAV) and delivered subretinally in a RhoP23H knock-in mouse model of ADRP. This results in significant mouse-to-human rhodopsin RNA replacement and is associated with a slowing of retinal degeneration. This provides proof of principle that synthetic mirtrons delivered by AAV are capable of reducing disease severity in vivo.

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