genetically. As first symptoms, patients typically experience weakness in the muscles of the limbs and loss of sensation in hands and feet. When the disease progresses, loss of muscular tissue occurs, leading to mild to severe motor handicap. The hereditary pattern of the disease is various: it can be transmitted from a healthy mother to her male children (X-linked inheritance), from one affected parent to (on average) 50% of his/her children (dominant inheritance), or from healthy parents, both carrier of a genetic mutation, to 25% of their progeny (recessive inheritance). Recessive forms are very rare in Switzerland and in Western Europe, while higher numbers are observed in ethnic groups where consanguineous marriages are more frequent. Since HPN is a clear genetic disorder, analysis of mutation can be performed directly on the DNA from patients, extracted for example from a few drops of their blood. The aim of our study is to identify and characterize novel disease-genes, by taking advantage of a series of recent and highly-parallel genetic technologies that are particularly well adapted for the study of consanguineous pedigrees.

We have collected the DNA of 46 consanguineous families with HPN, mainly from the Mediterranean basin and the Middle East. In selected patients and informative family members we have performed first a global genomic analysis to tag the regions of the genome likely to contain a mutation. Then, by taking advantage of the so-called Next Generation DNA sequencing technologies, we have directly analyzed the DNA sequence of patients and identified the molecular cause of the disease. Finally, based on the genetic data, we have functionally characterized the identified genes, in hopes of providing new insights into the mechanisms (and hence possible treatments) underlying peripheral neuropathies.

Our project makes use of next-generation technologies for DNA analyses to solve cases of concrete medical importance such as genetic diseases. Thanks to the support of Gebert Rüf Stiftung, we have applied such techniques to investigate the etiology of a rare, although handicapping, disorder such as HPN. Furthermore, we have taken advantage of the knowledge gained from this project to investigate another group of hereditary neurodegenerations, known as retinitis pigmentosa and allied diseases.

The project presented here is also a true interdisciplinary endeavor, involving clinicians, molecular geneticists and experts in the field of neurobiology. Therefore it represents a good subject for extramural support, as opposed to more classical research grants that are usually attributed to single individuals.

Collectively, we have obtained enough results to produce 8 scientific articles, describing, among other things, the identification of 3 new disease genes and the molecular causes of HPN and retinitis pigmentosa for a relatively large number of patients. Additional research, originating from data that were obtained during this project, is also currently carried out.

Nishiguchi KM, Tearle RG, Liu Y, Oh EC, Miyake N, Benaglio P, Harper S, Koskiniemi-Kuendig H, Venturini G, Sharon D, Koenekoop RK, Nakamura M, Kondo M, Ueno S, Yasuma T, Beckmann JS, Ikegawa S, Matsumoto N, Terasaki H, Berson EL, Katsanis N and Rivolta C (2013). Whole genome sequencing in patients with retinitis pigmentosa reveals pathogenic DNA structural changes and NEK2 as a new disease gene. PNAS (in press);
Azzedine H, Zavadakova P, Planté-Bordeneuve V, Vaz Pato M, Pinto N, Bartesaghi L, Zenker J, Poirot O, Bernard-Marissal N, Arnaud Gouttenoire E, Cartoni R, Title A, Venturini G, Médard JJ, Makowski E, Schöls L, Claeys KG, Stendel C, Roos A, Weis J, Dubourg O, Leal Loureiro J, Stevanin G, Said G, Amato A, Baraban J, Leguern E, Senderek J, Rivolta C, Chrast R. (2013). PLEKHG5 deficiency leads to an intermediate form of autosomal-recessive Charcot-Marie-Tooth disease. Hum Mol Genet (in press);
Corton M, Nishiguchi KM, Avila-Fernández A, Nikopoulos K, Riveiro-Alvarez R, Tatu SD, Ayuso C, Rivolta C. (2013). Exome sequencing of index patients with retinal dystrophies as a tool for molecular diagnosis. PLoS One:e65574;
Azzedine H, Senderek J, Rivolta C and Chrast R (2012). Molecular genetics of Charcot-Marie-Tooth disease: from genes to genomes. Molecular Syndromology 3:204-214;
Venturini G, Rose AM, Shah AZ, Bhattacharya SS and Rivolta C (2012). CNOT3 Is a Modifier of PRPF31 Mutations in Retinitis Pigmentosa with Incomplete Penetrance. PLoS Genetics 8:e1003040;
Nishiguchi KM and Rivolta C (2012). Genes associated with retinitis pigmentosa and allied diseases are frequently mutated in the general population. PLoS ONE: e41902;
Avila-Fernandez A, Corton M, Nishiguchi KM, Muñoz-Sanz N, Benavides-Mori B, Blanco-Kelly F, Riveiro-Alvarez R, Garcia-Sandoval B, Rivolta C and Ayuso C. (2012). Identification of a RP1 prevalent founder mutation and related phenotype in Spanish early-onset autosomal recessive retinitis patients. Ophthalmology 119:2616-21;
Langmann T, Di Gioia SA, Rau I, Stöhr H, Maksimovic NS, Corbo JC, Renner AB, Zrenner E, Kumaramanickavel G, Karlstetter M, Arsenijevic Y, Weber BHF, Gal A and Rivolta C (2010). Nonsense Mutations in FAM161A Cause RP28-Associated Recessive Retinitis Pigmentosa. The American Journal of Human Genetics 87: 376–381.

20minutes, 13.8.2010: Importante découverte vaudoise
Le Temps, 13.8.2010: Rétinite pigmentaire
sda, 12.8.2010: Identification du gène en cause dans la rétinite pigmentaire
AP Berne, 12.8.2010: Un espoire pour soigner la rétinite pigmentaire