De novo INF2 mutations expand the genetic spectrum of hereditary neuropathy with glomerulopathy

From the Neurogenetics Group, VIB-Department of Molecular Genetics (I.M., T.D., P.D.J., J.B.), and Laboratory of Neurogenetics, Institute Born-Bunge (I.M., T.D., P.D.J., J.B.), University of Antwerp, Antwerpen, Belgium
Neurology (Impact Factor: 8.29). 10/2013; 81(22). DOI: 10.1212/01.wnl.0000436615.58705.c9
Source: PubMed


Identification of mutations in the inverted formin-2 (INF2) gene in patients with Charcot-Marie-Tooth (CMT) disease combined with focal segmental glomerulosclerosis (FSGS) in order to expand the genetic and phenotypic spectrum.
We sequenced INF2 in 5 patients with CMT disease and FSGS. Mutations were subsequently screened in family members of the index patient and 264 control individuals.
In 3 patients, we detected 2 novel de novo INF2 mutations (p.Leu77Arg and p.Leu69_Ser72del) and a third, most likely de novo mutation (p.Gly114Asp). One of our patients displayed intellectual disability, a phenotypic characteristic not previously associated with INF2. The same patient also showed a more pronounced sensorineural hearing loss than described before.
In exon 2 of INF2, we identified 3 novel mutations that likely affect the protein structure and function. Our findings expand the genetic spectrum of INF2-associated disorders and broaden the associated phenotype with the co-occurrence of intellectual disability and more severe hearing loss than previously reported. De novo INF2 mutations may be more common in patients with CMT disease and FSGS in comparison to FSGS alone. Furthermore, renal dysfunction is more severe and starts earlier in life when associated with CMT disease. Our study confirms that INF2 mutations are a major cause of disease in patients with CMT disease and early signs of nephropathy. Diagnostic screening of INF2 is strongly recommended in isolated patients presenting with CMT disease and FSGS.

Download full-text


Available from: Jonathan Baets, Jul 13, 2014
  • [Show abstract] [Hide abstract]
    ABSTRACT: Mutations in the inverted formin-2 (INF2) gene were recently identified in patients with autosomal dominant intermediate Charcot-Marie-Tooth disease (DI-CMT) and focal segmental glomerulosclerosis (FSGS). Here, we identified a novel p.L132P INF2 mutation in a Korean family with DI-CMT and FSGS by whole exome sequencing. This mutation was cosegregated with affected individuals in the family and was not found in the 300 controls. The two affected members exhibited juvenile onset sensorimotor polyneuropathy and FSGS. Nerve conduction studies showed an intermediate range of motor nerve conduction velocities. We report a novel INF2 mutation in a family with DI-CMT and FSGS as the first case in Koreans. The INF2 mutation appears to be a major cause of CMT with FSGS.
    Journal of the Peripheral Nervous System 04/2014; 19(2). DOI:10.1111/jns5.12062 · 2.76 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Charcot-Marie-Tooth disease (CMT) is a clinically and genetically heterogeneous group of inherited disorders affecting motor and sensory nerves of the peripheral nervous system. CMT has been reported to be associated with renal diseases, mostly focal segmental glomerulosclerosis (FSGS). However, it was unknown whether these two clinical manifestations represent one common underlying disorder or separate disease entities. Several reports have shown a high prevalence of mutations (75%) in the inverted formin gene (INF2) in patients with CMT-associated glomerulopathy, suggesting that these mutations are a common cause of the dual phenotype. For this reason, we strongly suggest to screen for proteinuria in CMT patients, in order to identify patients with this renal-neurologic phenotype in an early stage, and to perform genetic testing for INF2 mutations.
    European Journal of Paediatric Neurology 08/2014; 19(1). DOI:10.1016/j.ejpn.2014.08.004 · 2.30 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Purpose of review: This article focuses on recent advances in Charcot-Marie-Tooth disease, in particular additions to the genetic spectrum, novel paradigms in molecular techniques and an update on therapeutic strategies. Recent findings: Several new Charcot-Marie-Tooth disease-causing genes have been recently identified, further enlarging the genetic diversity and phenotypic variability, including: SBF1, DHTKD1, TFG, MARS, HARS, HINT1, TRIM1, AIFM1, PDK3 and GNB4. The increasing availability and affordability of next-generation sequencing technologies has ramped up gene discovery and drastically changed genetic screening strategies. All large-scale trials studying the effect of ascorbic acid in Charcot-Marie-Tooth 1A have now been completed and were negative. Efforts have been made to design more robust outcome-measures for clinical trials. Promising results with lonaprisan, curcumin and histone deacetylase 6 inhibitors have been obtained in animal models. Summary: Charcot-Marie-Tooth is the most common form of inherited peripheral neuropathy and represents the most prevalent hereditary neuromuscular disorder. The genetic spectrum spans more than 70 genes. Gene discovery has been revolutionized recently by new high-throughput molecular technologies. In addition, the phenotypic diversity has grown tremendously. This is a major challenge for geneticists and neurologists. No effective therapy is available for Charcot-Marie-Tooth. Several large trials with ascorbic acid were negative but research into novel compounds continues.
    Current Opinion in Neurology 08/2014; 27(5). DOI:10.1097/WCO.0000000000000131 · 5.31 Impact Factor
Show more