Christophe Verny

Estimation of the Inbreeding Coefficient through Use of Genomic Data

Many linkage studies are performed in inbred populations, either small isolated populations or large populations with a long tradition of marriages between relatives. In such populations, there exist very complex genealogies with unknown loops. Therefore, the true inbreeding coefficient of an individual is often unknown. Good estimators of the inbreeding coefficient (f) are important, since it has been shown that underestimation of f may lead to false linkage conclusions. When an individual is genotyped for markers spanning the whole genome, it should be possible to use this genomic information to estimate that individuals f. To do so, we propose a maximum-likelihood method that takes marker dependencies into account through a hidden Markov model. This methodology also allows us to infer the full probability distribution of the identity-by-descent (IBD) status of the two alleles of an individual at each marker along the genome (posterior IBD probabilities) and provides a variance for the estimates. We simulate a full genome scan mimicking the true autosomal genome for (1) a first-cousin pedigree and (2) a quadruple-second-cousin pedigree. In both cases, we find that our method accurately estimates f for different marker maps. We also find that the proportion of genome IBD in an individual with a given genealogy is very variable. The approach is illustrated with data from a study of demyelinating autosomal recessive Charcot-Marie-Tooth disease.

In vivo evidence for the selective subcortical degeneration in Huntington's disease.

Although Huntingtons disease is largely considered to be a subcortical disease, there is no clear consensus on whether all deep grey matter loss is a direct downstream consequence of the massive degeneration of the medium-size spiny neurons in the striatum. Our aim was to characterise in vivo such preferential degeneration by analysing various distinct diffusion imaging measures including mean diffusivity, anisotropy, fibre orientation (using the information of the principal diffusion direction) and white matter tractography. All results converged to demonstrate the selective degeneration of connections in subcortical grey and white matter, degeneration which was likely to originate with the death of the striatal medium-size spiny neurons. Indeed, we found a significant increase of MD and FA in all the subcortical grey matter structures involved in the cortico-striato-thalamo-cortical loops. The atypical striatal and pallidal increase of FA was concurrent to a decrease of the dispersion of the fibre orientation, unambiguously characterising a preferential loss of connections along specific radiating directions from these structures while some others are comparatively spared. Analysis of striatal and pallidal white matter tracts revealed that striato-pallidal projections were the most affected. The ability of DTI to uncover the impact of such neurodegenerative disease on some specific neuronal/axonal populations is a further step towards the future definition of a surrogate marker of this disease. Beyond Huntingtons disease, we prove here that diffusion imaging technique, associated to adequate methodological analyses, can provide insight into any neurodegenerative disorder for which some neuronal populations or connections are selectively targeted over others.

OPA1 R445H mutation in optic atrophy associated with sensorineural deafness

The heterozygous R445H mutation in OPA1 was found in five patients with optic atrophy and deafness. Audiometry suggested that the sensorineural deafness resulted from auditory neuropathy. Skin fibroblasts showed hyperfragmentation of the mitochondrial network, decreased mitochondrial membrane potential, and adenosine triphosphate synthesis defect. In addition, OPA1 was found to be widely expressed in the sensory and neural cochlear cells of the guinea pig. Thus, optic atrophy and deafness may be related to energy defects due to a fragmented mitochondrial network. Ann Neurol 2005

Hereditary optic neuropathies share a common mitochondrial coupling defect

Hereditary optic neuropathies are heterogeneous diseases characterized by the degeneration of retinal ganglion cells leading to optic nerve atrophy and impairment of central vision. We found a common coupling defect of oxidative phosphorylation in fibroblasts of patients affected by autosomal dominant optic atrophy (mutations of OPA1), autosomal dominant optic atrophy associated with cataract (mutations of OPA3), and Lebers hereditary optic neuropathy, a disorder associated with point mutations of mitochondrial DNA complex I genes. Interestingly, the energetic defect was significantly more pronounced in Lebers hereditary optic neuropathy and autosomal dominant optic atrophy patients with a more complex phenotype, the so‐called plus phenotype. Ann Neurol 2008

Mitochondrial coupling defect in Charcot-Marie-Tooth type 2A disease.

Mutations of the mitofusin 2 gene (MFN2) may account for at least a third of the cases of Charcot–Marie–Tooth disease type 2 (CMT2). This study investigates mitochondrial cellular bioenergetics in MFN2‐related CMT2A.

Mitochondrial complex I deficiency in GDAP1-related autosomal dominant Charcot-Marie-Tooth disease (CMT2K)

Mutations in GDAP1, an outer mitochondrial membrane protein responsible for recessive Charcot-Marie-Tooth disease (CMT4A), have also been associated with CMT2K, a dominant form of the disease. The three CMT2K patients we studied carried a novel dominant GDAP1 mutation, C240Y (c.719G > A). Mitochondrial respiratory chain complex I activity in fibroblasts from CMT2K patients was 40% lower than in controls, whereas the tubular mitochondria were 33% larger in diameter and the mitochondrial mass was 20% greater. Thus, besides the regulatory role GDAP1 plays in mitochondrial network dynamics, it may also be involved in energy production and in the control of mitochondrial volume.

A genetic variation in the ADORA2A gene modifies age at onset in Huntington's disease ☆

Based on the pathophysiological role of adenosine A(2A) receptors in HD, we have evaluated the association of the 1976C/T single-nucleotide polymorphism in the ADORA2A gene (rs5751876) with residual age at onset (AAO) in HD. The study population consisted of 791 unrelated patients belonging to the Huntington French Speaking Network. The variability in AAO attributable to the CAG repeats number was calculated by linear regression using the log (AAO) as the dependent variable, and the respective rs5751876 genotypes as independent variables. We show that the rs5751876 variant significantly influences the variability in AAO. The R(2) statistic rose slightly but significantly (p=0.019) when rs5751876 T/T genotype was added to the regression model. Patients harbouring T/T genotype have an earlier AAO of 3.8 years as compared to C/C genotype (p=0.02). Our data thus strengthens the pathophysiological role of A(2A) receptors in Huntingtons disease.

Cognitive changes in asymptomatic carriers of the Huntington disease mutation gene

Huntington disease (HD) is a neurodegenerative disorder due to an excessive number of CAG repeats in the IT15 gene on chromosome 4. Studies of cognitive function in asymptomatic gene carriers have yielded contradictory results. This study compared cognitive performance in 44 subjects with the HD mutation (group of carriers) who had no clinical signs of HD and 39 at‐risk individuals without HD mutation (group of non‐carriers). Neuropsychological evaluation focused on global cognitive efficiency, psychomotor speed, attentional, executive and memory functions. Significant differences, with lower performances in the group of gene carriers, were detected for some measures of psychomotor speed, attention and executive functioning (all P < 0.01). More differences between groups were observed for memory measures, in particular on the California Verbal Memory Test. Complementing these observations, cognitive scores were correlated with age in the group of gene carriers, but not in the group of non‐carriers. This suggests that the cognitive changes precede the appearance of the motor and psychiatric symptoms in HD and that tests proved to be sensitive to early HD deficiencies are better suited than global cognitive efficiency scales to observe them.

Hereditary spastic paraplegia-like disorder due to a mitochondrial ATP6 gene point mutation.

Hereditary spastic paraplegia refers to a genetically heterogeneous syndrome. We identified five members of a family suffering from a late-onset spastic paraplegia-like disorder, carrying the homoplasmic m.9176 T>C mutation in the mitochondrial ATP6 gene. The clinical severity of the disease observed in the family was correlated with the biochemical and assembly defects of the ATP synthase. The m.9176 T>C mutation has been previously associated to Leigh syndrome or familial bilateral striatal necrosis. Other factors such as modifying genes may be involved in the phenotypic expression of the disease. The family belongs to the mitochondrial haplogroup J, previously shown to play a role in modulating the phenotype of mitochondrial diseases and be associated with longevity. Moreover other nuclear modifying genes or environmental factors may contribute to the disease phenotype. This finding extends the genetic heterogeneity of the hereditary spastic paraplegia together with the clinical spectrum of mutations of the ATP6 gene.

Mitochondrial dysfunction and pathophysiology of Charcot–Marie–Tooth disease involving GDAP1 mutations

Charcot-Marie-Tooth (CMT) disease represents a large group of clinically and genetically heterogeneous disorders leading to inherited peripheral neuropathies affecting motor and sensory neurons. Mutations in the ganglioside-induced differentiation-associated-protein 1 gene (GDAP1), which encodes a protein anchored to the mitochondrial outer membrane, are usually associated with the recessive forms of CMT disease and only rarely with the autosomal dominant forms. The function of GDAP1 is not fully understood but it plays a role in mitochondrial dynamics by promoting fission events. We present an overview of GDAP1 and the corresponding protein together with the complete spectrum of the 41 gene mutations described so far. We examine the relationship between the genotype and the phenotype in the various forms of CMT disease related to GDAP1 mutations, and discuss the pathophysiological hypotheses that link peripheral neuropathies to mitochondrial dysfunction and GDAP1 mutations. The meta-analysis of the literature reveals the great heterogeneity of phenotypic presentations and shows that the recessive forms of CMT disease, i.e. CMT4A and AR-CMT2, are far more severe than the dominant form, i.e. CMT2K. Among patients with recessive forms of the disease, those carrying truncating mutations are more seriously affected, often becoming wheelchair-bound before the end of the third decade. At the neuronal level, GDAP1 mutations may lead to perturbed axonal transport and impaired energy production as in other neurodegenerative diseases due to mutations in genes involved in mitochondrial dynamics.