title: Inverted formin 2-related Charcot-Marie-Tooth disease: extension of the mutational spectrum and pathological findings in Schwann cells and axons.
abstract: Mutations in the gene encoding inverted formin FH2 and WH2 domain-containing protein (INF2), a Cdc42 effector involved in the regulation of actin dynamics, cause focal segmental glomerulosclerosis (FSGS) and intermediate Charcot-Marie-Tooth neuropathy combined with FSGS (FSGS-CMT). Here, we report on six patients from four families with sensorimotor polyneuropathy and FSGS. Nerve conduction velocities were moderately slowed, and amplitudes of sensory and motor potentials were decreased. One patient had internal hydrocephalus and was intellectually disabled. Molecular genetic testing revealed two known and two novel missense mutations in the second and fourth exons of the INF2 gene. Investigations of one nerve biopsy confirmed the diagnosis of intermediate-type CMT and revealed occasional abnormal in- and outfoldings of myelin sheaths and expansions of the endoplasmic reticulum in axons and Schwann cells. While earlier reports suggested that mutations causing FSGS-CMT are restricted to exons 2 and 3 of the INF2 gene, we found one CMT-FSGS causing mutation (p.Glu184Lys) in exon 4 extending the critical region of INF2 for rapid CMT-FSGS molecular genetic diagnosis. Study of a nerve biopsy showed abnormalities that might be related to the known role of the INF2-binding partner CDC42 in myelination.
authors: Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany.|Department of Bioanalytics, Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V. Dortmund, Dortmund, Germany.
authors: Andreas
authors: A
authors: Roos
authors: Institute of Neuropathology, RWTH Aachen University Hospital, Aachen, Germany.
authors: Joachim
authors: J
authors: Weis
authors: Department of Pediatrics, University Hospital Freiburg, Freiburg, Germany.
authors: Rudolf
authors: R
authors: Korinthenberg
authors: Department of Pediatrics, Hospital Memmingen, Memmingen, Germany.
authors: Henry
authors: H
authors: Fehrenbach
authors: Department of Pediatrics, RWTH Aachen University Hospital, Aachen, Germany.
authors: Martin
authors: M
authors: Häusler
authors: Dr. John T. Macdonald Foundation, Department of Human Genetics and John P. Hussman Institute for Human Genomics, University of Miami Miller School of Medicine, Miami, FL, USA.
authors: Stephan
authors: S
authors: Züchner
authors: Department of Pediatrics, Medical University Graz, Graz, Austria.
authors: Christoph
authors: C
authors: Mache
authors: Department of Pediatrics, Medical University Graz, Graz, Austria.
authors: Holger
authors: H
authors: Hubmann
authors: Department of Orthopaedics, Medical University Vienna, Vienna, Austria.
authors: Michaela
authors: M
authors: Auer-Grumbach
authors: Friedrich-Baur Institute, Department of Neurology, Ludwig-Maximilians University Munich, Munich, Germany.
authors: Jan
authors: J
authors: Senderek
mesh_terms: D000293:Adolescent; D000328:Adult; D001369:Axons / Q000473:pathology*; D002607:Charcot-Marie-Tooth Disease / Q000150:complications / Q000235:genetics; D002648:Child; D005260:Female; D000080865:Formins; D005820:Genetic Testing; D005923:Glomerulosclerosis, Focal Segmental / Q000150:complications / Q000235:genetics*; D006801:Humans; D008840:Microfilament Proteins / Q000235:genetics*; D018482:Muscle, Skeletal / Q000473:pathology; D009154:Mutation / Q000235:genetics*; D010525:Peripheral Nerves / Q000000981:diagnostic imaging / Q000378:metabolism / Q000473:pathology; D012583:Schwann Cells / Q000473:pathology*; D014463:Ultrasonography; D055815:Young Adult
chemical_list: D000080865:Formins; C546959:INF2 protein, human; D008840:Microfilament Proteins
keywords: CDC42; CMTDIE; FSGS-CMT; INF2; actin dynamics; focally folded myelin