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Biomedical subjects

Arnold Munnich

Publications and source records attributed to Arnold Munnich.

At least 19 recordsLinked to original sources
PubMed2026

No Correlation Between Interferon Signaling and Cytosolic Mitochondrial DNA/RNA Leakage in Cultured Skin Fibroblasts of Patients With Mitochondrial Diseases.

Mitochondria have long been known to be involved in the regulation of innate immune response. We questioned whether cultured skin fibroblasts of patients suffering from mitochondrial diseases are valuable biological resources for the study of interferon signaling. Expression of interferon-stimulated genes was measured in control cells supplemented with interferon and in cultured fibroblasts of patients carrying pathogenic variants in mitochondrial disease-causing genes. Control fibroblasts showed a strong expression of interferon-stimulated genes in response to interferon, but only 43% of patients' fibroblasts displayed increased interferon stimulated genes scores. Cytosolic mitochondrial DNA and RNA were quantified by immunofluorescence and confocal microscopy. No correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA release could be established. We found that cultured skin fibroblasts represent a valuable biological resource for the investigation of interferon signaling, but that abnormal interferon signaling is not always observed in patients with mitochondrial diseases. At variance to gene silencing in control fibroblasts, the lack of correlation between elevated interferon response and cytosolic mitochondrial DNA or RNA leakage in patients' fibroblasts questions the relevance of cellular models as illustrators of pathological situations in humans.

Humans↗
PubMed2007

A novel recurrent mitochondrial DNA mutation in ND3 gene is associated with isolated complex I deficiency causing Leigh syndrome and dystonia.

Defects in NADH:ubiquinone oxidoreductase (complex I), the largest complex of the mitochondrial respiratory chain, account for most cases of respiratory chain deficiency in human. Complex I contains at least 45 subunits, 7 of which are encoded by mitochondrial DNA (mtDNA). Here we report a novel 10197G>A mutation of the ND3 gene in three unrelated families with Leigh syndrome (LS) or dystonia. Variable degrees of heteroplasmy were found in all tissues tested and a high percentage of mutant mtDNA was observed in muscle. The 10197G>A mutation modifies a hydrophobic alanine residue into a hydrophilic threonine (A47T) in a highly conserved domain of ND3 subunit. Furthermore, this defect could be transferred along with the mutant mtDNAs to rho degrees lymphoblastoid cells in cybrid experiments. However, nuclear modifier genes may also play a role in the phenotypic expression and severity of the 10197G>A mutation. The association of the 10197G>A ND3 mutation with an isolated biochemical defect involving complex I and the discovery of the 10197G>A mutation with a similar phenotype in three unrelated families establish its pathogenicity and demonstrate that the amino acid position A47 is important for the function of complex I. These results show that the 10197G>A mutation in the mitochondrial ND3 gene should be considered as a common mtDNA mutation responsible for LS and dystonia.

Adult↗
PubMed2007

Comprehensive survey of mutations in RP2 and RPGR in patients affected with distinct retinal dystrophies: genotype-phenotype correlations and impact on genetic counseling.

X-linked forms of retinitis pigmentosa (RP) (XLRP) account for 10 to 20% of families with RP and are mainly accounted for by mutations in the RP2 or RP GTPase regulator (RPGR) genes. We report the screening of these genes in a cohort of 127 French family comprising: 1) 93 familial cases of RP suggesting X-linked inheritance, including 48 out of 93 families with expression in females but no male to male transmission; 2) seven male sibships of RP; 3) 25 sporadic male cases of RP; and 4) two cone dystrophies (COD). A total of 5 out of the 93 RP families excluded linkage to the RP2 and RP3 loci and were removed form the cohort. A total of 14 RP2 mutations, 12 of which are novel, were identified in 14 out of 88 familial cases of RP and 1 out of 25 sporadic male case (4%). In 13 out of 14 of the familial cases, no expression of the disease was noted in females, while in 1 out of 14 families one woman developed RP in the third decade. A total of 42 RPGR mutations, 26 of which were novel, were identified in 80 families, including: 69 out of 88 familial cases (78.4%); 2 out of 7 male sibship (28.6%); 8 out of 25 sporadic male cases (32.0%); and 1 out of 2 COD. No expression of the disease was noted in females in 41 out of 69 familial cases (59.4%), while at least one severely affected woman was recognized in 28 out of 69 families (40.6%). The frequency of RP2 and RPGR mutations in familial cases of RP suggestive of X-linked transmission are in accordance to that reported elsewhere (RP2: 15.9% vs. 6-20%; RPGR: 78.4% vs. 55-90%). Interestingly, about 30% of male sporadic cases and 30% of male sibships of RP carried RP2 or RPGR mutations, confirming the pertinence of the genetic screening of XLRP genes in male patients affected with RP commencing in the first decade and leading to profound visual impairment before the age of 30 years.

Child↗
PubMed2007

Incidence and clinical features of X-linked Cornelia de Lange syndrome due to SMC1L1 mutations.

Cornelia de Lange syndrome (CdLS) is a multisystem developmental disorder characterized by facial dysmorphism, growth and mental retardation, microcephaly, and various malformations. Heterozygous mutations in the NIPBL gene have been detected in approximately 45% of affected individuals. Recently, a second CdLS gene, mapping to the X chromosome, has been identified: SMC1L1 (structural maintenance of chromosomes 1-like 1; or SMC1A). In order to estimate the incidence and refine the clinical presentation of X-linked CdLS, we have screened a series of 11 CdLS boys carrying no NIPBL anomaly. We have identified two novel de novo SMC1L1 missense mutations (c.587G>A [p.Arg196His] and c.3254A>G [p.Tyr1085Cys]). Our results confirm that SMC1L1 mutations cause CdLS and support the view that SMC1L1 accounts for a significant fraction of boys with unexplained CdLS. Furthermore, we suggest that SMC1L1 mutations have milder effects than NIPBL mutations with respect to pre- and postnatal growth retardation and associated malformations. If confirmed, these data may have important implications for directing mutation screening in CdLS.

Adolescent↗
PubMed2006

The Meckel-Gruber syndrome gene, MKS3, is mutated in Joubert syndrome.

Joubert syndrome (JS) is an autosomal recessive disorder characterized by cerebellar vermis hypoplasia associated with hypotonia, developmental delay, abnormal respiratory patterns, and abnormal eye movements. The association of retinal dystrophy and renal anomalies defines JS type B. JS is a genetically heterogeneous condition with mutations in two genes, AHI1 and CEP290, identified to date. In addition, NPHP1 deletions identical to those that cause juvenile nephronophthisis have been identified in a subset of patients with a mild form of cerebellar and brainstem anomaly. Occipital encephalocele and/or polydactyly have occasionally been reported in some patients with JS, and these phenotypic features can also be observed in Meckel-Gruber syndrome (MKS). MKS is a rare, autosomal recessive lethal condition characterized by central nervous system malformations (typically, occipital meningoencephalocele), postaxial polydactyly, multicystic kidney dysplasia, and ductal proliferation in the portal area of the liver. Since there is obvious phenotypic overlap between JS and MKS, we hypothesized that mutations in the recently identified MKS genes, MKS1 on chromosome 17q and MKS3 on 8q, may be a cause of JS. After mutation analysis of MKS1 and MKS3 in a series of patients with JS (n=22), we identified MKS3 mutations in four patients with JS, thus defining MKS3 as the sixth JS locus (JBTS6). No MKS1 mutations were identified in this series, suggesting that the allelism is restricted to MKS3.

Abnormalities, Multiple↗
PubMed2006

Allele dosage-dependent penetrance of RET proto-oncogene in an Israeli-Arab inbred family segregating Hirschsprung disease.

Hirschsprung disease (HSCR) is characterised by intestinal obstruction resulting from an absence of ganglion cells in the intestinal tract. The mutations in the major gene, RET, associated with isolated HSCR, are dominant loss-of-function mutations with incomplete penetrance and variable expressivity. We have ascertained a large inbred Israeli-Arab family segregating HSCR. Sequencing of the RET gene showed a splicing mutation, IVS6+5G- >A, in the homozygous state in all the females with severe forms of HSCR and in the heterozygous state in the male patient with short-segment HSCR. The recently described hypomorphic-RET predisposing allele, rs2435357, was transmitted in the heterozygous state to the male patient, but was not transmitted to the three affected females. Although the heterozygous IVS6+5G- >A is of low-penetrance for short-segment HSCR disease, the homozygous state is fully penetrant for total aganglionosis or long-segment HSCR. As in other inbred populations segregating a weakly penetrant RET allele (Mennonite), our findings support the hypothesis that the penetrance of RET gene mutations for the HSCR phenotype depends on: (i) the nature of the mutation, (ii) the allele dosage and (iii) modifier-loci.

Alleles↗
PubMed2006

Tequila, a neurotrypsin ortholog, regulates long-term memory formation in Drosophila.

Mutations in the human neurotrypsin gene are associated with autosomal recessive mental retardation. To further understand the pathophysiological consequences of the lack of this serine protease, we studied Tequila (Teq), the Drosophila neurotrypsin ortholog, using associative memory as a behavioral readout. We found that teq inactivation resulted in a long-term memory (LTM)-specific defect. After LTM conditioning of wild-type flies, teq expression transiently increased in the mushroom bodies. Moreover, specific inhibition of teq expression in adult mushroom bodies resulted in a reversible LTM defect. Hence, the Teq pathway is essential for information processing in Drosophila.

Amino Acid Sequence↗
PubMed2006

Three different ABCA4 mutations in the same large family with several consanguineous loops affected with autosomal recessive cone-rod dystrophy.

A large multiplex family presumably affected with autosomal recessive cone-rod dystrophy (CRD) was ascertained from Israel. In this family of Christian Arab ancestry with six consanguineous loops, linkage analysis failed to identify homozygosity in all six nuclear families at any of the three arCORD loci hitherto reported. However, homozygosity was found at the CORD3 locus for two nuclear families and the segregation of three distinct haplotypes at this locus in the whole pedigree suggested the alteration of the ABCA4 gene. This hypothesis was confirmed by the identification of three distinct mutations. Subsequently, with regard to the wide spectrum of autosomal recessive retinal dystrophies related to ABCA4 mutations, the natural history of the disease was revisited in all patients. Although the diagnosis of CRD was confirmed in 8/9 patients, the last one, aged of 34, displayed typical signs of Stargardt disease without extension to the peripheral retina. The results of this study emphasize the pitfalls of homozygosity mapping in highly inbred families when the heterozygote carrier frequency is particularly high in the general population.

ATP-Binding Cassette Transporters↗
PubMed2006

Circadian rhythm disorder in a rare disease: Smith-Magenis syndrome.

Smith-Magenis syndrome (SMS) is a clinically recognizable contiguous gene syndrome, caused by interstitial deletion of chromosome 17p11.2. The SMS phenotype include distinctive facial features, developmental delay and neurobehavioral abnormalities. The patients present major sleep disturbances ascribed to a phase shift of their circadian rhythm of melatonin with a paradoxical diurnal secretion of the hormone. Treatment with morning beta-blockers and evening melatonin reinstated a normally timed melatonin circadian rhythm, improved daytime behavior and restored normal sleep habits, resulting in a greatly improved quality of life for both SMS patients and their family. SMS is the demonstration of biological basis for sleep disorder in a genetic disease. Considering that clock genes mediate generation of circadian rhythms, we suggest that haploinsufficiency for a circadian system gene mapping to chromosome 17p11.2 may cause the inversion of circadian rhythm in SMS.

Child↗
PubMed2006

Molecular analysis of ANT1, TWINKLE and POLG in patients with multiple deletions or depletion of mitochondrial DNA by a dHPLC-based assay.

ANT1, TWINKLE and POLG genes affect mtDNA stability and are involved in autosomal dominant PEO, while mutations in POLG are responsible for numerous clinical presentations, including autosomal recessive PEO, sensory ataxic neuropathy, dysarthria and ophthalmoparesis (SANDO), spino-cerebellar ataxia and epilepsy (SCAE) or Alpers syndrome. In this study, we report on the mutational analysis of ANT1, TWINKLE and POLG genes in 15 unrelated patients, using a dHPLC-based protocol. This series of patients illustrates the large array of clinical presentations associated with mtDNA stability defects, ranging from isolated benign PEO to fatal Alpers syndrome. A total of seven different mutations were identified in six of 15 patients (40%). Six different recessive mutations were found in POLG, one in TWINKLE while no mutation was identified in ANT1. Among the POLG mutations, three are novel and include two missense and one frameshift changes. Seventeen neutral changes and polymorphisms were also identified, including four novel neutral polymorphisms. Overall, this study illustrates the variability of phenotypes associated with mtDNA stability defects, increases the mutational spectrum of POLG variants and provides an efficient and reliable detection protocol for ANT1, TWINKLE and POLG mutational screening.

Adenine Nucleotide Translocator 1↗
PubMed2006

Defective chondrocyte proliferation and differentiation in osteochondromas of MHE patients.

Multiple hereditary exostoses (MHE) is an autosomal dominant skeletal disorder caused by mutations in one of the two EXT genes and characterized by multiple osteochondromas that generally arise near the ends of growing long bones. Defective endochondral ossification is likely to be involved in the formation of osteochondromas. In order to investigate potential changes in chondrocyte proliferation and/or differentiation during this process, osteochondroma samples from MHE patients were obtained and used for genetic, morphological, immunohistological, and in situ hybridization studies. The expression patterns of IHH (Indian hedgehog) and FGFR3 (Fibroblast Growth Factor Receptor 3) were similar with transcripts expressed throughout osteochondromas. Expression of PTHR1 (Parathyroid Hormone Receptor 1) transcripts was restricted to a narrow zone of prehypertrophic chondrocytes. Numerous cells forming osteochondromas although resembling prehypertrophic chondrocytes, stained positively with an anti-proliferating cell nuclear antigen (PCNA) antibody. In addition, ectopic expression of collagen type I and abnormal presence of osteocalcin (OC), osteopontin (OP), and bone sialoprotein (BSP) were observed in the cartilaginous osteochondromas. These data indicate that most chondrocytes involved in the growth of osteochondromas can proliferate, and that some of them exhibit bone-forming cell characteristics. We conclude that in MHE, defective heparan sulfate biosynthesis caused by EXT mutations maintains the proliferative capacity of chondrocytes and promotes phenotypic modification to bone-forming cells.

Adolescent↗
PubMed2006

Father-to-daughter transmission of Cornelia de Lange syndrome caused by a mutation in the 5' untranslated region of the NIPBL Gene.

Cornelia de Lange syndrome (CdLS; also called Brachmann de Lange syndrome) is a developmental disorder characterized by typical facial dysmorphism, growth and mental retardation, microcephaly, and various malformations. Mutations in the NIPBL gene have been identified in approximately 40% of reported cases, suggesting either genetic heterogeneity or that some NIPBL mutations are not detected by current screening strategies. We screened a cohort of 21 patients with no previously identified NIPBL anomaly for mutations in the 5' untranslated region (5'UTR) and the proximal promoter of the NIPBL gene. We identified a heterozygous deletion-insertion mutation in exon 1, 321 nucleotides upstream of the translation initiation codon (c.-321_-320delCCinsA) in one affected girl and her mildly affected father. This mutation altered highly conserved nucleotides, was not found in 400 control alleles, arose de novo in the father, and cosegregated with the disease in the family. Using real-time quantitative PCR, we showed that NIPBL mRNA expression was lowered in patients' lymphocytes compared to control samples. Finally, we showed that, when subcloned into a luciferase reporter vector, the mutation leads to a significant reduction of reporter gene activity. Our results demonstrate that mutations in the 5' noncoding region of the NIPBL gene can be involved in the pathogenesis of CdLS. Mutations affecting this region of the gene might be associated with a milder phenotype.

5' Untranslated Regions↗
PubMed2006

Genetic characterisation of circulating fetal cells allows non-invasive prenatal diagnosis of cystic fibrosis.

OBJECTIVES: Cystic fibrosis (CF) is an autosomal recessive disease due to mutations in the cystic fibrosis transmembrane conductance regulator (CFTR) gene. The purpose of this study was to develop a molecular method to characterise both paternal and maternal CFTR alleles in DNA from circulating fetal cells (CFCs) isolated by ISET (isolation by size of epithelial tumour/trophoblastic cells). METHODS: The molecular protocol was defined by developing the F508del mutation analysis and addressing it both to single trophoblastic cells, isolated by ISET and identified by short tandem repeats (STR) genotyping, and to pooled trophoblastic genomes, thus avoiding the risk of allele drop out (ADO). This protocol was validated in 100 leucocytes from F508del carriers and subsequently blindly applied to the blood (5 mL) of 12 pregnant women, at 11 to 13 weeks of gestation, whose offspring had a 1/4 risk of CF. Ten couples were carriers of F508del mutation, while two were carriers of unknown CFTR mutations. RESULTS: Results showed that one fetus was affected, seven were heterozygous carriers of a CFTR mutation, and four were healthy homozygotes. These findings were consistent with those obtained by chorionic villus sampling (CVS). CONCLUSION: Our data show that the ISET-CF approach affords reliable prenatal diagnosis (PND) of cystic fibrosis and is potentially applicable to pregnant women at risk of having an affected child, thus avoiding the risk of iatrogenic miscarriage.

Alleles↗
PubMed2006

Academic impairment is the most frequent complication of neurofibromatosis type-1 (NF1) in children.

Neurofibromatosis type-1 (NF1) is a common genetic disorder associated with a variety of medical complications, cognitive impairments, and behavioral problems. One hundred and sixteen patients with NF1 (62 males, 54 females; mean age 12.4 years) and 80 typically developing children of the same ages (46 males, 34 females; mean age 11.5 years) were studied in terms of complications and learning impairment (one or more grade repetitions or school exclusion). Seventy of 116 patients had significant learning impairment. Classical complications were present in 53 patients including the three.

Adolescent↗
PubMed2006

Respiratory chain deficiency in a female with Aicardi-Goutières syndrome.

Aicardi-Goutières syndrome (AGS) is an early-onset progressive encephalopathy characterized by calcifications of the basal ganglia, white matter abnormalities, chronic cerebrospinal fluid (CSF) lymphocytosis, and/or a raised level of CSF interferon (INF)-alpha. We report a female with mitochondrial respiratory chain deficiency fulfilling the criteria of AGS. Disease onset was in the first year of age with seizures and psychomotor regression. To date, at 4 years of age, she presents a severe encephalopathy, increased INF-alpha in the CSF, and calcifications of basal ganglia on computerized tomography. Cerebral magnetic resonance imaging showed bilateral and symmetric hypersignal of the posterior white matter. A complex I deficiency of the mitochondrial respiratory chain was found in skeletal muscle, which was associated with a complex IV deficiency in cultured skin fibroblasts. The question of whether this oxidative phosphorylation deficiency is primary or secondary in AGS is open to debate. We suggest giving consideration to systematic evaluation of the mitochondrial respiratory chain in skeletal muscle and skin fibroblasts of other AGS patients.

Basal Ganglia↗
PubMed2006

Interstitial 9q22.3 microdeletion: clinical and molecular characterisation of a newly recognised overgrowth syndrome.

In the course of a systematic whole genome screening of patients with unexplained overgrowth syndrome by microarray-based comparative genomic hybridisation (array-CGH), we have identified two children with nearly identical 6.5 Mb-long de novo interstitial deletions at 9q22.32-q22.33. The clinical phenotype includes macrocephaly, overgrowth and trigonocephaly. In addition, both children present with psychomotor delay, hyperactivity and distinctive facial features. Further analysis with a high-resolution custom microarray covering the whole breakpoint intervals with fosmids mapped the deletion breakpoints within 100-kb intervals: although the deletion boundaries are different for the two patients, nearly the same genes are deleted in both cases. We suggest therefore that microdeletion of 9q22.32-q22.33 is a novel cause of overgrowth and mental retardation. Its association with distinctive facial features should help in recognising this novel phenotype.

Child, Preschool↗
PubMed2006

Discontinuity in the fall of left-handedness in a French population: a May '68 effect?

The fall in the prevalence of left-handedness with age has been attributed to the effect of forced dextrality on handwriting. The purpose of this study was to assess handwriting preference in a cohort of children and adult participants in order to study the correlation between age and incidence of sinistrality. A strong preference for right handwriting across all ages with a decrease in sinistrality with age (18% in those under 20 versus 3% in those over 60) was observed. This phenomenon was not continuous, and a dramatic drop at age 30-40 years might be attributed to changes in educational management during the 1960s, especially after the events of May 1968 in France.

Adolescent↗