scholarly journals Functional Consequences of Integrin Gene Mutations in Mice

2001 ◽  
Vol 89 (3) ◽  
pp. 211-223 ◽  
Author(s):  
Daniel Bouvard ◽  
Cord Brakebusch ◽  
Erika Gustafsson ◽  
Attila Aszódi ◽  
Therese Bengtsson ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Functional Consequences ◽  
Integrin Gene

scholarly journals Molecular Analysis of the ABCA4 Gene Mutations in Patients with Stargardt Disease Using Human Hair Follicles

2020 ◽  
Vol 21 (10) ◽  
pp. 3430
Author(s):  
Aneta Ścieżyńska ◽  
Marta Soszyńska ◽  
Michał Komorowski ◽  
Anna Podgórska ◽  
Natalia Krześniak ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Splice Site ◽  
Human Hair ◽  
Gene Mutations ◽  
Hair Follicles ◽  
Cdna Sequencing ◽  
Stargardt Disease ◽  
Protein Levels ◽  
Abca4 Gene ◽  
Functional Consequences

ABCA4 gene mutations are the cause of a spectrum of ABCA4 retinopathies, and the most common juvenile macular degeneration is called Stargardt disease. ABCA4 has previously been observed almost exclusively in the retina. Therefore, studying the functional consequences of ABCA4 variants has required advanced molecular analysis techniques. The aim of the present study was to evaluate whether human hair follicles may be used for molecular analysis of the ABCA4 gene splice-site variants in patients with ABCA4 retinopathies. We assessed ABCA4 expression in hair follicles and skin at mRNA and protein levels by means of real-time PCR and Western blot analyses, respectively. We performed cDNA sequencing to reveal the presence of full-length ABCA4 transcripts and analyzed ABCA4 transcripts from three patients with Stargardt disease carrying different splice-site ABCA4 variants: c.5312+1G>A, c.5312+2T>G and c.5836-3C>A. cDNA analysis revealed that c.5312+1G>A, c.5312+2T>G variants led to the skipping of exon 37, and the c.5836-3C>A variant resulted in the insertion of 30 nucleotides into the transcript. Our results strongly argue for the use of hair follicles as a model for the molecular analysis of the pathogenicity of ABCA4 variants in patients with ABCA4 retinopathies.

scholarly journals Characterisation of three novel CYP11B1 mutations in classic and non-classic 11β-hydroxylase deficiency

2014 ◽  
Vol 170 (5) ◽  
pp. 697-706 ◽  
Author(s):  
Seher Polat ◽  
Alexandra Kulle ◽  
Züleyha Karaca ◽  
Ilker Akkurt ◽  
Selim Kurtoglu ◽  
...  
Keyword(s):  
Expression System ◽  
Three Dimensional ◽  
Gene Mutations ◽  
Dimensional Structure ◽  
Hydroxylase Deficiency ◽  
Mutant Proteins ◽  
Maximum Reaction ◽  
Functional Consequences ◽  
21 Hydroxylase Deficiency

BackgroundCongenital adrenal hyperplasia (CAH) is one of the most common autosomal recessive inherited endocrine diseases. Steroid 11β-hydroxylase (P450c11) deficiency (11OHD) is the second most common form of CAH.AimThe aim of the study was to study the functional consequences of three novelCYP11B1gene mutations (p.His125Thrfs*8, p.Leu463_Leu464dup and p.Ser150Leu) detected in patients suffering from 11OHD and to correlate this data with the clinical phenotype.MethodsFunctional analyses were done by using a HEK293 cellin vitroexpression system comparing WT with mutant P450c11 activity. Mutant proteins were examinedin silicoto study their effect on the three-dimensional structure of the protein.ResultsTwo mutations (p.His125Thrfs*8 and p.Leu463_Leu464dup) detected in patients with classic 11OHD showed a complete loss of P450c11 activity. The mutation (p.Ser150Leu) detected in a patient with non-classic 11OHD showed partial functional impairment with 19% of WT activity.ConclusionFunctional mutation analysis enables the correlation of novelCYP11B1mutations to the classic and non-classic 11OHD phenotype respectively. Mutations causing a non-classic phenotype show typically partial impairment due to reduced maximum reaction velocity comparable with non-classic mutations in 21-hydroxylase deficiency. The increasing number of mutations associated with non-classic 11OHD illustrate that this disease should be considered as diagnosis in patients with otherwise unexplained hyperandrogenism.

scholarly journals Genetics of premature ovarian insufficiency and the association with X-autosome translocations

Reproduction ◽  
2020 ◽  
Vol 160 (4) ◽  
pp. R55-R64
Author(s):  
Adriana Di-Battista ◽  
Mariana Moysés-Oliveira ◽  
Maria Isabel Melaragno
Keyword(s):  
X Chromosome ◽  
Molecular Mechanisms ◽  
Ovarian Function ◽  
Single Gene ◽  
Position Effect ◽  
Gene Mutations ◽  
Premature Ovarian Insufficiency ◽  
Ovarian Insufficiency ◽  
Functional Consequences ◽  
Critical Regions

Premature ovarian insufficiency (POI) is the cessation of menstruation before the age of 40 and can result from different etiologies, including genetic, autoimmune, and iatrogenic. Of the genetic causes, single-gene mutations and cytogenetic alterations, such as X-chromosome aneuploidies and chromosome rearrangements, can be associated with POI. In this review, we summarize the genetic factors linked to POI and list the main candidate genes. We discuss the association of these genes with the ovarian development, the functional consequences of different mutational mechanisms and biological processes that are frequently disrupted during POI pathogenesis. Additionally, we focus on the high prevalence of X-autosome translocations involving the critical regions in Xq, known as POI1 and POI2, and discuss in depth the main hypotheses proposed to explain this association. Although the incorrect pairing of chromosomes during meiosis could lead to oocyte apoptosis, the reason for the prevalence of X-chromosome breakpoints at specific regions remains unclear. In most cases, studies on genes disrupted by balanced structural rearrangements cannot explain the ovarian failure. Thus, the position effect has emerged as a putative explanation for genetic mechanisms as translocations possibly result in changes in overall chromatin topology due to chromosome repositioning. Given the tremendous impact of POI on women’s quality of life, we highlight the value of investigations in to the interplay between ovarian function and gene regulation to deepen our understanding of the molecular mechanisms related to this disease, with the ultimate goal of improving patients’ care and assistance.

M1783 Functional Consequences of Autophagy Gene Mutations in Human Intestinal Epithelial Cells

2010 ◽  
Vol 138 (5) ◽  
pp. S-418
Author(s):  
Jeannette S. Messer ◽  
James P. Lodolce ◽  
Mark Logsdon ◽  
Sarah Bartulis ◽  
Stephanie Pineda ◽  
...  
Keyword(s):  
Epithelial Cells ◽  
Intestinal Epithelial Cells ◽  
Gene Mutations ◽  
Intestinal Epithelial ◽  
Autophagy Gene ◽  
Human Intestinal Epithelial Cells ◽  
Functional Consequences

Migraine: gene mutations and functional consequences

2007 ◽  
Vol 20 (3) ◽  
pp. 299-305 ◽  
Author(s):  
Arn MJM van den Maagdenberg ◽  
Joost Haan ◽  
Gisela M Terwindt ◽  
Michel D Ferrari
Keyword(s):  
Gene Mutations ◽  
Functional Consequences

scholarly journals Chromatin modifying gene mutations in follicular lymphoma

Blood ◽  
2018 ◽  
Vol 131 (6) ◽  
pp. 595-604 ◽  
Author(s):  
Michael R. Green
Keyword(s):  
Follicular Lymphoma ◽  
Germinal Center ◽  
Gene Mutations ◽  
Significant Heterogeneity ◽  
B Cell Differentiation ◽  
Disease Biology ◽  
Sequencing Studies ◽  
Target Disease ◽  
Attractive Therapeutic Target ◽  
Functional Consequences

Abstract Follicular lymphoma (FL) is an indolent malignancy of germinal center B cells. Although the overall survival of FL patients has recently improved with the introduction of novel therapies, there is significant heterogeneity in patient outcome and a need for rationally designed therapeutic strategies that target disease biology. Next-generation sequencing studies have identified chromatin modifying gene (CMG) mutations as a hallmark of FL, highlighting epigenetic modifiers as an attractive therapeutic target in this disease. Understanding the complex roles of these mutations will be central to identifying and adaptively targeting associated vulnerabilities. Recent studies have provided insight into the functional consequences of the most frequently mutated CMGs (KMT2D, CREBBP, and EZH2) and point to a role for these events in modifying normal B-cell differentiation programs and impeding germinal center exit. However, the majority of FL tumors serially acquire multiple CMG mutations, suggesting that there is a level of cross talk or cooperation between these events that has not yet been defined. Here, I review the current state of knowledge on CMG mutations in FL, discuss their potential as therapeutic targets, and offer my perspective on unexplored areas that should be considered in the future.

Functional consequences of perforin gene mutations in 22 patients with familial haemophagocytic lymphohistiocytosis

2002 ◽  
Vol 117 (4) ◽  
pp. 965-972 ◽  
Author(s):  
Jérôme Feldmann ◽  
Françoise Le Deist ◽  
Marie Ouachée-Chardin ◽  
Stéphanie Certain ◽  
Sarah Alexander ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Haemophagocytic Lymphohistiocytosis ◽  
Functional Consequences ◽  
Familial Haemophagocytic Lymphohistiocytosis

scholarly journals Counterregulatory responses to hypoglycemia in patients with maturity-onset diabetes of the young caused by HNF-1alpha gene mutations (MODY3)

2001 ◽  
pp. 45-49 ◽  
Author(s):  
E Guenat ◽  
G Seematter ◽  
J Philippe ◽  
E Temler ◽  
E Jequier ◽  
...  
Keyword(s):  
Gene Mutations ◽  
Glucose Production ◽  
Glucagon Secretion ◽  
Insulin Dependent Diabetes Mellitus ◽  
Endogenous Glucose Production ◽  
Dependent Diabetes Mellitus ◽  
Plasma Glucagon ◽  
Functional Consequences ◽  
Insulin Dependent ◽  
Endogenous Glucose

Mutations of HNF-1alpha lead to severe beta cell dysfunction, resulting in decreased glucose-induced insulin secretion. HNF-1alpha is also expressed in liver, kidney and pancreatic alpha cells, but the functional consequences of HNF-1alpha mutations in these organs remain unknown. We therefore assessed the counterregulatory responses to hypoglycemia in six patients with HNF-1alpha mutations (MODY3), five patients with non-insulin-dependent diabetes mellitus (NIDDM) and in nine healthy controls. Plasma glucagon concentrations and endogenous glucose production were measured every 15 min during a hyperinsulinemic clamp with progressive hypoglycemia. Plasma glucagon concentrations were similar at basal glycemia (73+/-6, 69+/-5 and 69+/-7 ng/l) and reached peak values of 88+/-9, 88+/-11 and 89+/-7 ng/l at a glycemia of 3.6 mmol/l in MODY3 patients, patients with NIDDM and controls respectively (NS). Suppression of endogenous glucose production by insulin was blunted in MODY3 patients (3.3+/-1.2 micromol/kg per min) and in patients with NIDDM (4.4+/-0.6 micromol/kg per min) compared with controls (1.7+/-0.5 micromol/kg per min, P<0.05 compared with both MODY3 patients and patients with NIDDM). During hypoglycemia, endogenous glucose production increased to 8.6+/-2.1, 8.8+/-0.7 and 7.0+/-1.0 micromol/kg per min in MODY3 patients, patients with NIDDM and controls respectively (all NS). These data indicate that mutations of HNF-1alpha in MODY3 do not result in a decreased glucagon secretion or alterations of glucose production during hypoglycemia.

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