Expanding the genetic landscape of inherited peripheral neuropathies: identification of new genes and phenotypes
16 December 2016
UAntwerp, Campus Drie Eiken, Building Q, Promotiezaal - Universiteitsplein 1 - 2610 Wilrijk (Antwerp) (route: UAntwerpen, Campus Drie Eiken
4:00 PM - 6:00 PM
Peter De Jonghe, Jonathan Baets
PhD defence Inès Mademan - Department of Biomedical Sciences
The inherited peripheral neuropathies (IPN) are a group of disorders causing progressive axonal degeneration in the peripheral nervous system (PNS). Because of the length-dependent degeneration of peripheral nerves, symptoms like muscle atrophy, weakness and sensory loss usually start in the most distal parts of the limbs. As a group, IPN are the most common inherited neuromuscular disorders with an estimated prevalence of 1/2500 individuals.
The IPN are clinically very heterogeneous, based on the involvement of certain nerve fibers they can be subdivided into three main categories, although a certain degree of overlap is observed. The largest group are the hereditary motor and sensory neuropathies (HMSN), also known as Charcot-Marie-Tooth disease (CMT), the smaller categories are the hereditary motor neuropathies (HMN) and the hereditary sensory and autonomic neuropathies (HSAN). Also major genetic heterogeneity is seen within the IPN with different types of inheritance and around 90 causal genes currently known encoding proteins that span a wide range of functions. Even though a large number of causal genes are implicated, still a considerable proportion of patients stays genetically undefined. Especially in the smaller groups of HMN and HSAN only around 20-30% of patients have a precise genetic diagnosis today.
The aim of this thesis is to gain insight into the genetic factors that contribute to axonal degeneration in the PNS by identifying novel genes and newly associated phenotypes using next-generation sequencing (NGS) technologies.
In two studies the genetic and clinical spectrum was expanded by identifying novel mutations with NGS. Mutations in HNRNPA1 were found to be associated with HMN and atypical amyotrophic lateral sclerosis phenotypes. Moreover, loss-of-function mutations in SYNE1 occur more frequently than previously assumed and cause a brought continuum of phenotypes. The novel causal ATL3 gene, previously not implicated in human disease, was identified in dominantly inherited HSAN with bone destruction. Finally, conventional sequencing techniques allowed the detection of additional mutations in INF2 as well as broadening the clinical picture of HMSN with focal glomerulosclerosis.
These studies will help to discover networks of related disease genes and underlying pathomechanisms in order to improve molecular diagnostics, prognosis determination, genetic counseling and eventually the development of a curative therapy that is still nonexistent.