12539
2012
eng
3567-3583
135
article
1
2016-01-26
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Myelin is dependent on the Charcot–Marie–Tooth Type 4H disease culprit protein FRABIN/FGD4 in Schwann cells
Studying the function and malfunction of genes and proteins associated with inherited forms of peripheral neuropathies has provided multiple clues to our understanding of myelinated nerves in health and disease. Here, we have generated a mouse model for the peripheral neuropathy Charcot–Marie–Tooth disease type 4H by constitutively disrupting the mouse orthologue of the suspected culprit gene FGD4 that encodes the small RhoGTPase Cdc42-guanine nucleotide exchange factor Frabin. Lack of Frabin/Fgd4 causes dysmyelination in mice in early peripheral nerve development, followed by profound myelin abnormalities and demyelination at later stages. At the age of 60 weeks, this was accompanied by electrophysiological deficits. By crossing mice carrying alleles of Frabin/Fgd4 flanked by loxP sequences with animals expressing Cre recombinase in a cell type-specific manner, we show that Schwann cell-autonomous Frabin/Fgd4 function is essential for proper myelination without detectable primary contributions from neurons. Deletion of Frabin/Fgd4 in Schwann cells of fully myelinated nerve fibres revealed that this protein is not only required for correct nerve development but also for accurate myelin maintenance. Moreover, we established that correct activation of Cdc42 is dependent on Frabin/Fgd4 function in healthy peripheral nerves. Genetic disruption of Cdc42 in Schwann cells of adult myelinated nerves resulted in myelin alterations similar to those observed in Frabin/Fgd4-deficient mice, indicating that Cdc42 and the Frabin/Fgd4–Cdc42 axis are critical for myelin homeostasis. In line with known regulatory roles of Cdc42, we found that Frabin/Fgd4 regulates Schwann cell endocytosis, a process that is increasingly recognized as a relevant mechanism in peripheral nerve pathophysiology. Taken together, our results indicate that regulation of Cdc42 by Frabin/Fgd4 in Schwann cells is critical for the structure and function of the peripheral nervous system. In particular, this regulatory link is continuously required in adult fully myelinated nerve fibres. Thus, mechanisms regulated by Frabin/Fgd4–Cdc42 are promising targets that can help to identify additional regulators of myelin development and homeostasis, which may crucially contribute also to malfunctions in different types of peripheral neuropathies.
Brain
10.1093/brain/aws275
23171661
urn:nbn:de:bvb:20-opus-125390
Brain 2012: 135; 3567–3583. doi:10.1093/brain/aws275
Michael Horn
Reto Baumann
Jorge A. Pereira
Páris N. M. Sidiropoulos
Christian Somandin
Hans Welzl
Claudia Stendel
Tessa Lühmann
Carsten Wessig
Klaus V. Toyka
João B. Relvas
Jan Senderek
Ueli Suter
eng
uncontrolled
Frabin/Fgd4
eng
uncontrolled
myelination
eng
uncontrolled
hereditary motor and sensory neuropathy
eng
uncontrolled
Charcot–Marie–Tooth disease
eng
uncontrolled
Rho-GTPase Cdc42
Krankheiten
open_access
Neurologische Klinik und Poliklinik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12539/Abdelmohsen_Genome Announc.-2015-Horn.pdf
12196
2013
eng
92
14
article
1
2015-11-13
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Facioscapulohumeral muscular dystrophy and Charcot-Marie-Tooth neuropathy 1A-evidence for "double trouble" overlapping syndromes
Background: We report on a patient with genetically confirmed overlapping diagnoses of CMT1A and FSHD. This case adds to the increasing number of unique patients presenting with atypical phenotypes, particularly in FSHD. Even if a mutation in one disease gene has been found, further genetic testing might be warranted in cases with unusual clinical presentation.
Case presentation: The reported 53 years old male patient suffered from walking difficulties and foot deformities first noticed at age 20. Later on, he developed scapuloperoneal and truncal muscle weakness, along with atrophy of the intrinsic hand and foot muscles, pes cavus, claw toes and a distal symmetric hypoesthesia. Motor nerve conduction velocities were reduced to 20 m/s in the upper extremities, and not educible in the lower extremities, sensory nerve conduction velocities were not attainable. Electromyography showed both, myopathic and neurogenic changes. A muscle biopsy taken from the tibialis anterior muscle showed a mild myopathy with some neurogenic findings and hypertrophic type 1 fibers. Whole-body muscle MRI revealed severe changes in the lower leg muscles, tibialis anterior and gastrocnemius muscles were highly replaced by fatty tissue. Additionally, fatty degeneration of shoulder girdle and straight back muscles, and atrophy of dorsal upper leg muscles were seen. Taken together, the presenting features suggested both, a neuropathy and a myopathy. Patient's family history suggested an autosomal dominant inheritance. Molecular testing revealed both, a hereditary motor and sensory neuropathy type 1A (HMSN1A, also called Charcot-Marie-Tooth neuropathy 1A, CMT1A) due to a PMP22 gene duplication and facioscapulohumeral muscular dystrophy (FSHD) due to a partial deletion of the D4Z4 locus (19 kb).
Conclusion: Molecular testing in hereditary neuromuscular disorders has led to the identification of an increasing number of atypical phenotypes. Nevertheless, finding the right diagnosis is crucial for the patient in order to obtain adequate medical care and appropriate genetic counseling, especially in the background of arising curative therapies.
BMC Medical Genetics
10.1186/1471-2350-14-92
1471-2350
urn:nbn:de:bvb:20-opus-121963
BMC Medical Genetics 2013, 14:92. doi:10.1186/1471-2350-14-92
Olivia Schreiber
Peter Schneiderat
Wolfram Kress
Bernd Rautenstrauss
Jan Senderek
Bendikt Schoser
Maggie C. Walter
eng
uncontrolled
D4Z4 partial deletion
eng
uncontrolled
sensory neuropathy
eng
uncontrolled
hereditary motor
eng
uncontrolled
disease
eng
uncontrolled
phenotype
eng
uncontrolled
FSHD
eng
uncontrolled
myopathy
eng
uncontrolled
patient
eng
uncontrolled
duplication
eng
uncontrolled
diagnosis
eng
uncontrolled
facioscapulohumeral muscular dystrophy
eng
uncontrolled
Charcot-Marie-Tooth neuropathy 1A
eng
uncontrolled
hereditary motor and sensory neuropathy
eng
uncontrolled
double trouble
eng
uncontrolled
overlapping syndrome
Menschliche Anatomie, Zytologie, Histologie
open_access
Institut für Humangenetik
Universität Würzburg
https://opus.bibliothek.uni-wuerzburg.de/files/12196/010_Schreiber_BMC_Medical_Genetics.pdf