Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease

Brenner, Michael; Johnson, Anne B.; Boespflug‐Tanguy, Odile; Rodriguez, Diana; Goldman, James E.; Messing, Albee

doi:10.1038/83679

Cited by 610 publications

(509 citation statements)

References 24 publications

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“…It has been previously reported with AD patients and considered causative for AD due to its de novo appearance [1,3]. However, the patient's parents and elder brother had a normal base sequence.…”

Section: Discussionmentioning

confidence: 94%

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Infantile Onset Alexander Disease with Normal Head Circumference: A Genetically Proven Case Report

Goyal¹

2014

JCDR

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A 16-month-old boy presented to our genetic OPD for evaluation of developmental regression and seizures. He was second in birth order, born to non consanguineous couple at term after normal vaginal delivery with birth weight of 2.8 kg. Mother's antenatal and perinatal history was uneventful. There was no history of any drug intake during pregnancy. He had attained social smile and neck holding at appropriate ages. He developed seizure at four months of age followed by significant regression in motor and cognitive skills whereby he lost neck holding and unable to recognise parents. Seizure was continuous and difficult to manage. Presently, at 16 monthss of age, he has partial neck holding, has no speech or interaction or recognition of parents. Parents gave a history of generalized spasticity of the body since six months of age. The patient has a six year old elder brother, intelligent, with normal development. There was no similar history in any family members from both sides of parents. On examination at 16 months of age, there were no dysmorphic features. Spasticity of upper and lower limbs with peripheral contractures at ankles was noted [Table/ Fig-1]. His weight, length and head circumference were 7.5 kg (between -2 and -3 SD), 72 cm (between -2 to -3 SD) and 46 cm (between 0 to -1 SD), respectively. There was no hepato-splenomegaly or any neurocutaneous stigmata. His body tone was increased with intermittent tightening. Deep tendon reflexes were exaggerated in both upper and lower limbs with extensor planter at ankle joints.Blood investigations including high performance liquid chromatography (HPLC) of serum amino acids, urine organic acid profile, serum ammonia and lactate level and thyroid function tests were within normal limit. Renal function tests, liver function test, hearing evaluation, ultrasonography abdomen were normal. Visual evoked potential (VEP) was subnormal with increased latencies. Magnetic resonance imaging ( MRI) brain showed signal alteration of white matter, predominantely in the bilateral frontal regions also involving basal ganglia. There was hypointense line along the ventricular margin and areas of diffusion restriction in the bilateral lentiform nucleus and frontal white matter with cystic dilatation of cavum septum pellucidum [Table/ Fig-2a&b]. Features were suggestive of Infantile form of Alexander disease (AD). Mutation analysis was advised. Consent was obtained from each of the participating members of the family in this study for genetic evaluation. A standard salting out protocol was followed for DNA isolation from the peripheral venous whole blood. The coding portion of the GFAP was amplified by polymerase chain reactions using nine set of primers. primer designing was done by Primer-3 software. The Paediatrics SectionInfantile Onset Alexander Disease with Normal Head Circumference: A Genetically Proven Case Report aBstRaCt Alexander disease (AD) is an autosomal dominant leukodystrophy which predominantly affects infants and children. The infantile form comprises the most c...

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Section: Discussionmentioning

confidence: 94%

“…Rosenthal fibers are protein aggregates containing GFAP, ubiquitin, heat shock protein hsp-27, and B-crystallin [2]. Mutation in the GFAPgene encodes GFAP protein has been proven to cause AD [3,4]. Three forms are recognized according to the age of clinical presentations: infantile, juvenile, and adult.…”

Section: Discussionmentioning

confidence: 99%

Infantile Onset Alexander Disease with Normal Head Circumference: A Genetically Proven Case Report

Goyal¹

2014

JCDR

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“…These astrocytic inclusions were later found to be identical to Rosenthal fibers [2]. The presence of GFAP in Rosenthal fibers led to the identification of mutations of the gene encoding GFAP as the cause of Alexander disease [4]. Rosenthal fibers, which are hyaline eosinophilic rods, are present throughout the central nervous system (CNS) in Alexander disease.…”

Section: Discussionmentioning

confidence: 99%

Juvenile Alexander Disease: a Case Report

Özkaya

Akcan

Aydemir

et al. 2012

EAJM

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Alexander disease is a rare autosomal recessive disorder that is characterized by degeneration of the white matter in the central nervous system. Alexander disease is a leukodystrophy that is usually observed in early childhood but rarely in adults. It is characterized by megalencephaly, demyelinization and multiple Rosenthal fibers. Specific magnetic resonance imaging (MRI) findings and genetic investigations are necessary to diagnose the disorder. Signs of leukodystrophy were found in the bilateral white matter on a brain MRI of our four-year-old patient. He had megalencephaly since birth. We use this case to discuss Alexander disease.Key Words: Alexander disease, Megalencephaly, Leukodystrophy, Pediatric neurology ÖzetAlexander hastalığı, nadir görülen ve santral sinir sisteminde beyaz cevherin dejenerasyonu ile karakterize otozomal resesif bir rahatsız-lıktır. Alexander hastalığı, genellikle çocukluk çağında nadir olarakta erişkinlerde görülen bir lökodistrofidir. Megalensefali, demyelinizasyon ve çok sayıda Rosenthal lifleri ile karakterizedir. Hastalığın tanısın-da spesifik magnetik rezonans (MRI) bulguları ve genetik araştırmalar faydalı olabilir. Dört yaşındaki olgunun MRI incelemesinde bilateral frontal beyaz cevherde lökodistrofik değişiklikler gözlenmiştir. İnfant döneminden bu yana megalensefali bulguları olguda gözlenmiştir. Bu olgunun yardımıyla, Alexander hastalığını tartışacağız.

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“…ALX, a rare disorder of the central nervous system, was found to be associated with mutations of the GFAP gene [31]. The hallmark of Alexander disease is Rosenthal fibers (RFs), which are eosinophilic, round or oblong bodies within the cytoplasm of astrocytes [30,32,33].…”

Section: Gfap Is Able To Coassemble With Nestin and Vimentinmentioning

confidence: 99%

Redistribution of GFAP and αB-crystallin after thermal stress in C6 glioma cell line

Tseng

Lee

et al. 2006

J Biomed Sci

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SummarySome intermediate filament (IF) proteins expressed in the development of glia include nestin, vimentin, and glial fibrillary acidic protein (GFAP). However, GFAP is the major intermediate filament protein of mature astrocytes. To determine the organization of GFAP in glial cells, rat GFAP cDNA tagged with enhanced green fluorescent protein (EGFP) was transfected into the rat C6 glioma cell line. After selection, two stable C6-EGFP-GFAP cell lines were established. Stable C6-EGFP-GFAP cell lines with or without heat shock treatment were analyzed by immunocytochemistry, electron microscopy, and Western blot analysis. In the transient transfection study, EGFP-GFAP transiently expressed in C6 cells formed punctate aggregations in the cytoplasm right after transfection, but gradually a filamentous structure of EGFP-GFAP was observed. The protein level of nestin in the C6-EGFP-GFAP stable clone was similar to that in the pEGFP-C1 transfected C6 stable clones and non-transfected C6 cells, whereas the level of vimentin was reduced in Western blotting. Interestingly, the expression level of small heat shock protein aB-crystallin in C6-EGFP-GFAP cells was also enhanced after transfection. Immunostaining patterns of C6-EGFP-GFAP cells showed that GFAP was dispersed as a fine filamentous structure. However, after heat shock treatment, GFAP formed IF bundles in C6-EGFP-GFAP cells. In the meantime, aB-crystallin also colocalized with IF bundles of GFAP in C6-EGFP-GFAP cells. The heat-induced GFAP reorganization we found suggested that small heat shock protein aB-crystallin may play a functional role regulating the cytoarchitecture of GFAP.

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Mutations in GFAP, encoding glial fibrillary acidic protein, are associated with Alexander disease

Cited by 610 publications

References 24 publications

Infantile Onset Alexander Disease with Normal Head Circumference: A Genetically Proven Case Report

Infantile Onset Alexander Disease with Normal Head Circumference: A Genetically Proven Case Report

Juvenile Alexander Disease: a Case Report

Redistribution of GFAP and αB-crystallin after thermal stress in C6 glioma cell line

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