The frequency of a rare mutant allele and the level of allelic association between this allele an... more The frequency of a rare mutant allele and the level of allelic association between this allele and one or several closely linked markers are frequently measured in genetic epidemiology. Both quantities are related to the time elapsed since the appearance of the mutation in the population and the intrinsic growth rate of the mutation (which may be different from the average population growth rate). Here, we develop a method that uses these two kinds of genetic data to perform a joint estimation of the age of the mutation and the minimum growth rate that is compatible with its present frequency. In absence of demographic data, it provides a useful estimate of population growth rate. When such data are available, contrasts among estimates from several loci allow demographic processes, affecting all loci similarly, to be distinguished from selection, affecting loci differently. Testing these estimates on populations for which data are available for several disorders shows good congruenc...
Objective:To identify the gene defect in patients with hypomyelination with atrophy of the basal ... more Objective:To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations.Methods:We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening. We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression.Results:Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy. The majority of patients had a known Roma ethnic background. Single nucleotide polymorphism array analysis in 5 patients identified one large overlapping homozygous region on chromosome 13. WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1. Sanger sequencing confirmed homozygosity for this variant in all ...
The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) con... more The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease.
... Median motor nerve conduction velocity was normal in the parents and markedly reduced in the ... more ... Median motor nerve conduction velocity was normal in the parents and markedly reduced in the children ranging from 6 to 15 m/s with distal latency of 8.8 to 13.6 ms. Sural nerve biopsy in the 13-year-old boy showed severe loss of myelinated fibres. ...
The frequency of a rare mutant allele and the level of allelic association between this allele an... more The frequency of a rare mutant allele and the level of allelic association between this allele and one or several closely linked markers are frequently measured in genetic epidemiology. Both quantities are related to the time elapsed since the appearance of the mutation in the population and the intrinsic growth rate of the mutation (which may be different from the average population growth rate). Here, we develop a method that uses these two kinds of genetic data to perform a joint estimation of the age of the mutation and the minimum growth rate that is compatible with its present frequency. In absence of demographic data, it provides a useful estimate of population growth rate. When such data are available, contrasts among estimates from several loci allow demographic processes, affecting all loci similarly, to be distinguished from selection, affecting loci differently. Testing these estimates on populations for which data are available for several disorders shows good congruenc...
Objective:To identify the gene defect in patients with hypomyelination with atrophy of the basal ... more Objective:To identify the gene defect in patients with hypomyelination with atrophy of the basal ganglia and cerebellum (H-ABC) who are negative for TUBB4A mutations.Methods:We performed homozygosity mapping and whole exome sequencing (WES) to detect the disease-causing variant. We used a Taqman assay for population screening. We developed a luciferase reporter construct to investigate the effect of the promoter mutation on expression.Results:Sixteen patients from 14 families from different countries fulfilling the MRI criteria for H-ABC exhibited a similar, severe clinical phenotype, including lack of development and a severe epileptic encephalopathy. The majority of patients had a known Roma ethnic background. Single nucleotide polymorphism array analysis in 5 patients identified one large overlapping homozygous region on chromosome 13. WES in 2 patients revealed a homozygous deletion in the promoter region of UFM1. Sanger sequencing confirmed homozygosity for this variant in all ...
The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) con... more The exosome is a multi-protein complex, required for the degradation of AU-rich element (ARE) containing messenger RNAs (mRNAs). EXOSC8 is an essential protein of the exosome core, as its depletion causes a severe growth defect in yeast. Here we show that homozygous missense mutations in EXOSC8 cause progressive and lethal neurological disease in 22 infants from three independent pedigrees. Affected individuals have cerebellar and corpus callosum hypoplasia, abnormal myelination of the central nervous system or spinal motor neuron disease. Experimental downregulation of EXOSC8 in human oligodendroglia cells and in zebrafish induce a specific increase in ARE mRNAs encoding myelin proteins, showing that the imbalanced supply of myelin proteins causes the disruption of myelin, and explaining the clinical presentation. These findings show the central role of the exosomal pathway in neurodegenerative disease.
... Median motor nerve conduction velocity was normal in the parents and markedly reduced in the ... more ... Median motor nerve conduction velocity was normal in the parents and markedly reduced in the children ranging from 6 to 15 m/s with distal latency of 8.8 to 13.6 ms. Sural nerve biopsy in the 13-year-old boy showed severe loss of myelinated fibres. ...
Uploads