scholarly journals A novel mutation in the GFAP gene expands the phenotype of Alexander disease

2019 ◽  
Vol 56 (12) ◽  
pp. 846-849 ◽  
Author(s):  
Carlos Casasnovas ◽  
Edgard Verdura ◽  
Valentina Vélez ◽  
Agatha Schlüter ◽  
Albert Pons-Escoda ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Alexander Disease ◽  
Missense Mutations ◽  
Adult Onset ◽  
Astrocytoma Cell ◽  
Cerebral Mri ◽  
Novel Variant ◽  
Bulbar Symptoms ◽  
Characteristic Signal

BackgroundAlexander disease, an autosomal dominant leukodystrophy, is caused by missense mutations in GFAP. Although mostly diagnosed in children, associated with severe leukoencephalopathy, milder adult forms also exist.MethodsA family affected by adult-onset spastic paraplegia underwent neurological examination and cerebral MRI. Two patients were sequenced by whole exome sequencing (WES). A candidate variant was functionally tested in an astrocytoma cell line.ResultsThe novel variant in GFAP (Glial Fibrillary Acidic Protein) N-terminal head domain (p.Gly18Val) cosegregated in multiple relatives (LOD score: 2.7). All patients, even those with the mildest forms, showed characteristic signal changes or atrophy in the brainstem and spinal cord MRIs, and abnormal MRS. In vitro, this variant did not cause significant protein aggregation, in contrast to most Alexander disease mutations characterised so far. However, cell area analysis showed larger size, a feature previously described in patients and mouse models.ConclusionWe suggest that this variant causes variable expressivity and an attenuated phenotype of Alexander disease type II, probably associated with alternative pathogenic mechanisms, that is, astrocyte enlargement. GFAP analysis should be considered in adult-onset neurological presentations with pyramidal and bulbar symptoms, in particular when characteristic findings, such as the tadpole sign, are present in MRI. WES is a powerful tool to diagnose atypical cases.

A novel mutation in the GFAP gene in a familial adult onset Alexander disease

2007 ◽  
Vol 254 (9) ◽  
pp. 1278-1280 ◽  
Author(s):  
Andrea Salmaggi ◽  
Andrea Botturi ◽  
Elena Lamperti ◽  
Marina Grisoli ◽  
Rita Fischetto ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Alexander Disease ◽  
Adult Onset

scholarly journals Functional consequence of a novel Y129C mutation in a patient with two contradictory melanocortin-2-receptor mutations

2009 ◽  
Vol 160 (4) ◽  
pp. 705-710 ◽  
Author(s):  
Li F Chan ◽  
Teng-Teng Chung ◽  
Ahmed F Massoud ◽  
Louise A Metherell ◽  
Adrian J L Clark
Keyword(s):  
Cell Surface ◽  
Novel Mutation ◽  
Surface Expression ◽  
Cell Surface Expression ◽  
Missense Mutations ◽  
Intracellular Loop ◽  
Spastic Quadriplegia ◽  
Activating Mutation ◽  
Glucocorticoid Deficiency

ContextFamilial glucocorticoid deficiency (FGD) is a rare autosomal recessive disease, characterised by isolated glucocorticoid deficiency in the absence of mineralocorticoid deficiency. Inactivating mutations in the ACTH receptor (melanocortin-2-receptor, MC2R) are well described and account for ∼25% of cases. By contrast, activating MC2R mutations are extremely rare.PatientWe report a child of Saudi Arabian origin who was diagnosed with FGD following hypoglycaemic episodes that resulted in spastic quadriplegia.Methods and resultsMC2R gene analysis revealed an unusual combination of two homozygous missense mutations, consisting of the novel mutation Y129C and the previously described F278C activating mutation. Parents were heterozygous at both of these sites. In vitro analysis of the Y129C mutation using a fluorescent cell surface assay showed that this mutant was unable to reach the cell surface in CHO cells stably transfected with MC2R accessory protein (MRAP), despite the demonstration of an interaction with MRAP by co-immunoprecipitation. The double mutant Y129C-F278C also failed to traffic to the cell surface.ConclusionThe tyrosine residue at position 129 in the second intracellular loop is critical in MC2R folding and/or trafficking to the cell surface. Furthermore, the absence of cell surface expression of MC2R would account for the lack of activation of the receptor due to the F278C mutation located at the C-terminal tail. We provide a novel molecular explanation for a child with two opposing mutations causing severe FGD.

scholarly journals A Novel Mutation of GFAP Causing Adult-Onset Alexander Disease

2019 ◽  
Vol 10 ◽  
Author(s):  
Andrea Ciammola ◽  
Davide Sangalli ◽  
Jenny Sassone ◽  
Barbara Poletti ◽  
Laura Carelli ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Alexander Disease ◽  
Adult Onset

Adult onset Alexander disease with a novel variant (S398F) in the glial fibrillary acidic protein gene

2009 ◽  
Vol 49 (6) ◽  
pp. 358-363 ◽  
Author(s):  
Yoshimasa Sueda ◽  
Tetsuya Takahashi ◽  
Kazuhide Ochi ◽  
Toshiho Ohtsuki ◽  
Michito Namekawa ◽  
...  
Keyword(s):  
Glial Fibrillary Acidic Protein ◽  
Protein Gene ◽  
Alexander Disease ◽  
Acidic Protein ◽  
Adult Onset ◽  
Novel Variant

Parkinsonism phenotype in a family with adult onset Alexander disease and a novel mutation of GFAP

2020 ◽  
Vol 195 ◽  
pp. 105893
Author(s):  
D. Vázquez-Justes ◽  
J. Peñalva-García ◽  
R. López ◽  
R. Mitjana ◽  
R. Begue ◽  
...  
Keyword(s):  
Novel Mutation ◽  
Alexander Disease ◽  
Adult Onset

scholarly journals Activation of a Cryptic Splice Site of GFAP in a Patient With Adult-Onset Alexander Disease

2021 ◽  
Vol 7 (6) ◽  
pp. e626
Author(s):  
Eiichiro Amano ◽  
Tomokatsu Yoshida ◽  
Ikuko Mizuta ◽  
Jun Oyama ◽  
Shingo Sakashita ◽  
...  
Keyword(s):  
Splice Site ◽  
Late Onset ◽  
Splice Site Mutation ◽  
Alexander Disease ◽  
Splice Acceptor Site ◽  
Acceptor Site ◽  
Missense Mutations ◽  
Adult Onset ◽  
Splice Acceptor ◽  
Site Mutation

Background and ObjectiveAlexander disease (ALXDRD) is an autosomal dominant neurologic disorder caused by mutations in the glial fibrillary acidic protein (GFAP) gene and is pathologically defined by Rosenthal fiber accumulation. Most mutations are exonic missense mutations, and splice site mutations are rare. We report a very-late-onset autopsied case of adult-onset ALXDRD with a novel splice site mutation.MethodsGenetic testing of GFAP was performed by Sanger sequencing. Using autopsied brain tissues, GFAP transcript analysis was performed.ResultsThe patient presented mild upper motor neuron symptoms in contrast to the severe atrophy of spinal cord and medulla oblongata. The patient had c.619-1G>A mutation, which is located in the canonical splice acceptor site of intron 3. The brain RNA analysis identified the r.619_621del (p.Glu207del) mutation, which is explained by the activation of the cryptic splice acceptor site in the second and third nucleotides from the 5′ end of the exon 4.DiscussionGFAP gene expression analysis is necessary to clarify the effects of intronic mutations on splicing, even if they are in canonical splice sites. This case showed a much milder phenotype than those in previous cases with missense mutations at Glu207, thereby expanding the clinical spectrum of ALXDRD with Glu207 mutation.

A Novel Mutation Glyl672→Arg in Type 2A and a Homozygous Mutation in Type 2B von Willebrand Disease

1996 ◽  
Vol 76 (02) ◽  
pp. 253-257 ◽  
Author(s):  
Takeshi Hagiwara ◽  
Hiroshi Inaba ◽  
Shinichi Yoshida ◽  
Keiko Nagaizumi ◽  
Morio Arai ◽  
...  
Keyword(s):  
Missense Mutation ◽  
Novel Mutation ◽  
Point Mutations ◽  
Japanese Patients ◽  
Von Willebrand Disease ◽  
Homozygous Mutation ◽  
Missense Mutations ◽  
Reaction Products ◽  
Type 3 ◽  
Von Willebrand

SummaryGenetic materials from 16 unrelated Japanese patients with von Willebrand disease (vWD) were analyzed for mutations. Exon 28 of the von Willebrand factor (vWF) gene, where point mutations have been found most frequent, was screened by various restriction-enzyme analyses. Six patients were observed to have abnormal restriction patterns. By sequence analyses of the polymerase chain-reaction products, we identified a homozygous R1308C missense mutation in a patient with type 2B vWD; R1597W, R1597Q, G1609R and G1672R missense mutations in five patients with type 2A; and a G1659ter nonsense mutation in a patient with type 3 vWD. The G1672R was a novel missense mutation of the carboxyl-terminal end of the A2 domain. In addition, we detected an A/C polymorphism at nucleotide 4915 with HaeIII. There was no particular linkage disequilibrium of the A/C polymorphism, either with the G/A polymorphism at nucleotide 4391 detected with Hphl or with the C/T at 4891 detected with BstEll.

Characterization of the Original Christmas Disease Mutation (Cysteine 206 → Serine): From Clinical Recognition to Molecular Pathogenesis

1992 ◽  
Vol 67 (01) ◽  
pp. 063-065 ◽  
Author(s):  
Sherryl A M Taylor ◽  
Jacalyn Duffin ◽  
Cherie Cameron ◽  
Jerome Teitel ◽  
Bernadette Garvey ◽  
...  
Keyword(s):  
Nucleotide Substitution ◽  
Novel Mutation ◽  
Factor Ix ◽  
Causative Mutation ◽  
Coding Region ◽  
Body Of Knowledge ◽  
Polymerase Chain ◽  
Splice Junctions

SummaryChristmas disease was first reported as a distinct clinical entity in two manuscripts published in 1952 (1, 2). The eponym associated with this disorder, is the surname of the first patient examined in detail and reported by Biggs and colleagues in a paper describing the clinical and laboratory features of seven affected individuals (3). This patient has severe factor IX coagulant deficiency (less than 0.01 units/ml) and no detectable circulating factor IX antigen (less than 0.01 units/ml). Coding sequence and splice junctions of the factor IX gene from this patient have been amplified in vitro through the polymerase chain reaction (PCR). One nucleotide substitution was identified at nucleotide 30,070 where a guanine was replaced by a cytosine. This mutation alters the amino acid encoded at position 206 in the factor IX protein from cysteine to serine. The non conservative nature of this substitution, the absence of this change in more than 200 previously sequenced factor IX genes and the fact that the remainder of the coding region of this gene was normal, all provide strong circumstantial evidence in favour of this change being the causative mutation in this patient. The molecular characterization of this novel mutation in the index case of Christmas disease, contributes to the rapidly expanding body of knowledge pertaining to Christmas disease pathogenesis.

Identification of new ARMC5 missense mutations in Primary Bilateral Macronodular Adrenal Hyperplasia (PBMAH) and their functional studies in vitro

2018 ◽  
Author(s):  
Anna Vaczlavik ◽  
Stephanie Espiard ◽  
Marie-Odile North ◽  
Ludivine Drougat ◽  
Marthe Rizk-Rabin ◽  
...  
Keyword(s):  
Missense Mutations ◽  
Adrenal Hyperplasia ◽  
Functional Studies
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