Lekbir Baala - Academia.edu (original) (raw)

Papers by Lekbir Baala

Research paper thumbnail of Autisme, génétique et anomalies de la fonction synaptique

Pathologie Biologie, Oct 1, 2010

Autism is a neurodevelopmental disorder characterized by a deficit of language and communication ... more Autism is a neurodevelopmental disorder characterized by a deficit of language and communication both associated with a restricted repertoire of activities and interests. The current prevalence of autistic disorder stricto sensu is estimated at 1/500 whereas autism spectrum disorders (ASD) increases up to 1/150 to 1/200. Mental deficiency (MD) and epilepsy are present in numerous autistic individuals. Consequently, autism is as a major public health issue. Autism was first considered as a non biological disease; however various rational approaches for analysing epidemiological data suggested the possibility of the influence of genetic factors. In 2003, this hypothesis was clearly illustrated by the characterization of genetic mutations transmitted through a mendelian manner. Subsequently, the glutamate synapse appeared as a preferential causal target in autism because the identified genes encoded proteins present in this structure. Strikingly, the findings that an identical genetic dysfunction of the synapse might also explain some MD suggested the possibility of a genetic comorbidity between these neurodevelopmental conditions. To date, various identified genes are considered indifferently as "autism" or "MD" genes. The characterization of mutations in the NLGN4X gene in patients with Asperger syndrome, autism without MD, or MD without autism, was the first example. It appears that a genetic continuum between ASD on one hand, and between autism and MD on the other hand, is present. Consequently, it is likely that genes already involved in MD will be found mutated in autistic patients and will represent future target for finding new factors in autism.

Research paper thumbnail of Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis

Nature Genetics, Mar 11, 2007

Neural progenitor proliferation and migration influence brain size during neurogenesis. We report... more Neural progenitor proliferation and migration influence brain size during neurogenesis. We report an autosomal recessive microcephaly syndrome cosegregating with a homozygous balanced translocation between chromosomes 3p and 10q, and we show that a position effect at the breakpoint on chromosome 3 silences the eomesodermin transcript (EOMES), also known as T-box-brain2 (TBR2). Together with the expression pattern of EOMES in the developing human brain, our data suggest that EOMES is involved in neuronal division and/or migration. Thus, mutations in genes encoding not only mitotic and apoptotic proteins but also transcription factors may be responsible for malformative microcephaly syndromes.

Research paper thumbnail of Implication D'Un Gene Du Spliceosome Dans Un Cas De Deficience Mentale Severe ?

Le Centre pour la Communication Scientifique Directe - HAL - Archive ouverte HAL, Feb 2, 2012

Research paper thumbnail of Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: A tight junction disease

Research paper thumbnail of Sensitivity and specificity of heat and moisture exchange filters sampling for SARS-CoV-2 detection in mechanically ventilated COVID-19 patients

Journal of Microbiology, Immunology and Infection

We assessed the sensitivity and specificity of SARS-CoV-2 detection by polymerase chain reaction ... more We assessed the sensitivity and specificity of SARS-CoV-2 detection by polymerase chain reaction in heat and moisture exchange filters (HMEF) in mechanically ventilated COVID-19 patients. We showed that testing HMEF might obviate the need for a tracheal sample to affirm that a patient is not ready to end isolation.

Research paper thumbnail of Autisme, génétique et anomalies de la fonction synaptique

Pathologie Biologie, 2010

Autism is a neurodevelopmental disorder characterized by a deficit of language and communication ... more Autism is a neurodevelopmental disorder characterized by a deficit of language and communication both associated with a restricted repertoire of activities and interests. The current prevalence of autistic disorder stricto sensu is estimated at 1/500 whereas autism spectrum disorders (ASD) increases up to 1/150 to 1/200. Mental deficiency (MD) and epilepsy are present in numerous autistic individuals. Consequently, autism is as a major public health issue. Autism was first considered as a non biological disease; however various rational approaches for analysing epidemiological data suggested the possibility of the influence of genetic factors. In 2003, this hypothesis was clearly illustrated by the characterization of genetic mutations transmitted through a mendelian manner. Subsequently, the glutamate synapse appeared as a preferential causal target in autism because the identified genes encoded proteins present in this structure. Strikingly, the findings that an identical genetic dysfunction of the synapse might also explain some MD suggested the possibility of a genetic comorbidity between these neurodevelopmental conditions. To date, various identified genes are considered indifferently as "autism" or "MD" genes. The characterization of mutations in the NLGN4X gene in patients with Asperger syndrome, autism without MD, or MD without autism, was the first example. It appears that a genetic continuum between ASD on one hand, and between autism and MD on the other hand, is present. Consequently, it is likely that genes already involved in MD will be found mutated in autistic patients and will represent future target for finding new factors in autism.

Research paper thumbnail of The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome

Nature Genetics, 2007

Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) synd... more Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) syndrome belong to the group of developmental autosomal recessive disorders that are associated with primary cilium dysfunction. Using SNP mapping, we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS, and we show that inactivation of the mouse ortholog Rpgrip1l (Ftm) recapitulates the cerebral, renal and hepatic defects of CORS and MKS. In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4, known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy). In addition, the RPGRIP1L missense mutations found in CORS individuals diminishes the interaction between RPGRIP1L and nephrocystin-4. Our findings show that mutations in RPGRIP1L can cause the multiorgan phenotypic abnormalities found in CORS or MKS, which therefore represent a continuum of the same underlying disorder. Joubert syndrome is an autosomal recessive multisystem disease characterized by cerebellar ataxia, developmental delay, hypotonia, irregular breathing pattern, eye movement abnormalities 1 and cerebellar vermis hypoplasia and dysplasia with accompanying brainstem defects. When visualized on axial images using magnetic resonance imaging (MRI), the brainstem defects give rise to the 'molar tooth sign' (MTS) 2. A related disorder, CORS, is defined by the features of Joubert syndrome with the addition of one or more of the following: renal involvement (nephronophthisis or cystic renal dysplasia), retinal dystrophy, coloboma, polydactyly or liver fibrosis. Nephronophthisis (NPHP), the most common genetic cause of chronic renal failure in children, is characterized by interstitial fibrosis and medullary cyst formation. Disease-causing mutations have been identified in six genes (NPHP1-NPHP6) whose protein products are known to localize to primary cilia 3-5. Joubert syndrome is a genetically heterogeneous condition with recessive mutations in two known genes: AHI1 (ref. 6) and NPHP6 (also known as CEP290) 4,5. In addition, a homozygous NPHP1 deletion shown to be the most common cause of juvenile NPHP has been identified in a subset of individuals with NPHP and Joubert syndrome 7-9 who present with a milder form of the neurological symptoms 10. Two more loci, JBTS1 (CORS1; ref. 11) and JBTS2 (CORS2; ref. 12), have been mapped to chromosomes 9q34.3 and 11p12-11q13.3, respectively.

Research paper thumbnail of Pleiotropic Effects of CEP290 (NPHP6) Mutations Extend to Meckel Syndrome

The American Journal of Human Genetics, 2007

Research paper thumbnail of The Meckel-Gruber Syndrome Gene, MKS3, Is Mutated in Joubert Syndrome

The American Journal of Human Genetics, 2007

Research paper thumbnail of Both Recessive and Dominant Forms of Anhidrotic/Hypohidrotic Ectodermal Dysplasia Map to Chromosome 2q11-q13

The American Journal of Human Genetics, 1999

Research paper thumbnail of Moroccan family with Joubert syndrome: a

Research paper thumbnail of Cartographie par autozygotie et identification de gènes de maladies rares dans la population marocaine : application aux génodermatoses et à une anomalie de développement cérébral

Les maladies genetiques transmises selon le mode autosomique recessif constituent un veritable pr... more Les maladies genetiques transmises selon le mode autosomique recessif constituent un veritable probleme de sante publique au Maroc du fait du taux eleve de consanguinite. Tirant partie de la consanguinite, la cartographie par autozygotie permet de localiser pour les identifier les genes de ces maladies. Ces puissantes methodes nous ont permis de localiser et d'identifier les genes de trois maladies autosomiques recessives : 1) deux genodermatoses dont une forme recessive de dysplasie ectodermique anhidrotique (DEA) et un syndrome associant ichtyose et cholangite sclerosante (NISCH), et 2) un syndrome de microcephalie avec une agenesie du corps calleux, une craniostenose et un retard mental. Nos travaux ont contribue a mettre en evidence l'importance de l'analyse des maladies genetiques rares dans les populations a fort taux de consanguinite.

Research paper thumbnail of Case Report: Co-infection with SARS-CoV-2 and influenza H1N1 in a patient with acute respiratory distress syndrome

F1000Research, 2020

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 ... more Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and has been a global public health concern. Co-infection of SARS-CoV-2 and other respiratory syndrome has been rarely reported. We report coinfection of SARS-CoV-2 and 2009 H1N1 Influenza strain in a French patient with pneumonia leading to acute respiratory distress syndrome. The patient also had a medical history of pulmonary sarcoidosis with a restrictive ventilatory syndrome, which would be a supplementary risk to develop a poor outcomes. This case highlights the possible coinfection of two severe SARS-CoV-2 and influenza H1N1 viruses, which presents a higher risk to extend the care duration. The overlapping clinical features of the two respiratory syndromes is a challenge, and awareness is required to recommend an early differential diagnosis.

Research paper thumbnail of Cartographie par autozygotie et identification de gènes de maladies rares dans la population marocaine : application aux génodermatoses et à une anomalie de développement cérébral

Research paper thumbnail of A homozygous AHI1 gene mutation (p.Thr304AsnfsX6) in a consanguineous Moroccan family with Joubert syndrome: a case report

Journal of Medical Case Reports, 2015

Introduction: Joubert syndrome is a rare congenital disorder characterized by brain malformation,... more Introduction: Joubert syndrome is a rare congenital disorder characterized by brain malformation, developmental delay with hypotonia, ocular motor apraxia, and breathing abnormalities. Joubert syndrome is a genetically highly heterogeneous ciliopathy disorder with 23 identified causative genes. The diagnosis is based on brain imaging showing the "molar tooth sign" with cerebellar vermis agenesis. We describe a consanguineous Moroccan family with three affected siblings (18-year-old boy, 13-year-old girl, and 10-year-old boy) showing typical signs of Joubert syndrome, and attempt to identify the underlying genetic defect in this family. Methods: We performed genome-wide homozygosity mapping using a high-resolution array followed by targeted Sanger sequencing to identify the causative gene. Results: This approach found three homozygous regions, one including the AHI1 gene. Direct sequencing of the 26 coding exons of AHI1 revealed a homozygous mutation (p.Thr304AsnfsX6) located in exon 7 present in the three Joubert syndrome-affected Moroccan siblings. Of more interest, this truncating mutation was previously reported in patients with compound heterozygous Joubert syndrome originating from Spain (one patient) and from the Netherlands (two patients), suggesting a possible founder effect or mutational hotspot. Conclusions: Combined homozygosity mapping and targeted sequencing allowed the rapid detection of the disease-causing mutation in the AHI1 gene in this family affected with a highly genetically heterogeneous disorder. Carriers of the same truncating mutation (p.Thr304AsnfsX6), originating from Spain and the Netherlands, presented variable clinical characteristics, thereby corroborating the extreme heterogeneity of Joubert syndrome.

Research paper thumbnail of Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis

Nature Genetics, 2007

Neural progenitor proliferation and migration influence brain size during neurogenesis. We report... more Neural progenitor proliferation and migration influence brain size during neurogenesis. We report an autosomal recessive microcephaly syndrome cosegregating with a homozygous balanced translocation between chromosomes 3p and 10q, and we show that a position effect at the breakpoint on chromosome 3 silences the eomesodermin transcript (EOMES), also known as T-box-brain2 (TBR2). Together with the expression pattern of EOMES in the developing human brain, our data suggest that EOMES is involved in neuronal division and/or migration. Thus, mutations in genes encoding not only mitotic and apoptotic proteins but also transcription factors may be responsible for malformative microcephaly syndromes.

Research paper thumbnail of Autosomal recessive anhidrotic ectodermal dysplasia in a large Moroccan family

Journal of Medical Genetics, 1998

We studied a large Moroccan family in which anhidrotic ectodermal dysplasia is transmitted as an ... more We studied a large Moroccan family in which anhidrotic ectodermal dysplasia is transmitted as an autosomal recessive trait. Fourteen family members, both males and females, were affected and they all had a common ancestor. Linkage analysis by homozygosity mapping in this family will permit the gene localisation of this rare form of anhidrotic ectodermal dysplasia.

Research paper thumbnail of Homozygosity Mapping of a Locus for a Novel Syndromic Ichthyosis to Chromosome 3q27-q28

Journal of Investigative Dermatology, 2002

Ichthyosis is a heterogeneous group of skin disorders characterized by abnormal epidermal scaling... more Ichthyosis is a heterogeneous group of skin disorders characterized by abnormal epidermal scaling. Occasionally, extracutaneous features are associated. A novel autosomal recessive ichthyosis syndrome is described here with scalp hypotrichosis, scarring alopecia, sclerosing cholangitis, and leukocyte vacuolization in two inbred kindreds of Moroccan origin. We also report the mapping of the diseased gene to a 21.2 cM interval of chromosome 3q27-q28. Homo zygosity for polymorphic markers has enabled us to reduce the genetic interval to a 16.2 cM region. Furthermore, comparison of mutant chromosomes in the two families has suggested a common ancestral mutant haplotype. This linkage disequilibrium has reduced the genetic interval encompassing the diseased gene to less than 9.5 cM maximum. Further study of additional families from the same geographic area will hopefully reduce the genetic interval as well as help in the cloning of the gene involved in this rare disorder.

Research paper thumbnail of Spectrum of HLXB9 gene mutations in Currarino syndrome and genotype-phenotype correlation

Human Mutation, 2008

Communicated by Sergio Ottolenghi Currarino syndrome (CS) is a rare congenital malformation descr... more Communicated by Sergio Ottolenghi Currarino syndrome (CS) is a rare congenital malformation described in 1981 as the association of three main features: typical sacral malformation (sickle-shaped sacrum or total sacral agenesis below S2), hindgut anomaly, and presacral tumor. In addition to the triad, tethered cord and/or lipoma of the conus are also frequent and must be sought, as they may lead to severe complications if not treated. The HLXB9 gene, located at 7q36, is disease-causing. It encodes the HB9 transcription factor and interacts with DNA through a highly evolutionarily conserved homeodomain early in embryological development. Thus far, 43 different heterozygous mutations have been reported in patients fulfilling CS criteria. Mutation detection rate is about 50%, and reaches 90% in familial cases. Here, we report 23 novel mutations in 26 patients among a series of 50 index cases with CS, and review mutational reports published since the identification of the causative gene. Three cytogenetic anomalies encompassing the HLXB9 gene are described for the first time. Truncating mutations (frameshifts or nonsense mutations) represent 57% of those identified, suggesting that haploinsufficiency is the basis of CS. No obvious genotype-phenotype correlation can be drawn thus far. Genetic heterogeneity is suspected, since at least 19 of the 24 patients without HLXB9 gene mutation harbor subtle phenotypic variations.

Research paper thumbnail of Autosomal dominant anhidrotic ectodermal dysplasias at the EDARADD locus

Human Mutation, 2007

Communicated by Sergio Ottolenghi Anhidrotic ectodermal dysplasia (EDA) is a disorder of ectoderm... more Communicated by Sergio Ottolenghi Anhidrotic ectodermal dysplasia (EDA) is a disorder of ectodermal differentiation characterized by sparse hair, abnormal or missing teeth, and inability to sweat. X-linked EDA is the most common form, caused by mutations in the EDA gene, which encodes ectodysplasin, a member of the tumor necrosis factor (TNF) family. Autosomal dominant and recessive forms of EDA have been also described and are accounted for by two genes. Mutations in EDAR, encoding a TNF receptor (EDAR) cause both dominant and recessive forms. In addition, mutations in a recently identified gene, EDARADD, encoding EDAR-associated death domain (EDARADD) have been shown to cause autosomal recessive EDA. Here, we report a large Moroccan family with an autosomal dominant EDA. We mapped the disease gene to chromosome 1q42.2-q43, and identified a novel missense mutation in the EDARADD gene (c.335T4G, p.Leu112Arg). Thus, the EDARADD gene accounts for both recessive and dominant EDA. EDAR is activated by its ligand, ectodysplasin, and uses EDARADD to build an intracellular complex and activate nuclear factor kappa B (NF-kB). We compared the functional consequences of the dominant (p.Leu112Arg) and recessive mutation (p.Glu142Lys), which both occurred in the death domain (DD) of EDARADD. We demonstrated that the p.Leu112Arg mutation completely abrogated NF-kB activation, whereas the p.Glu142Lys retained the ability to significantly activate the NF-kB pathway. The p.Leu112Arg mutation is probably a dominant negative form as its cotransfection impaired the wild-type EDARADD's ability to activate NF-kB. Our results confirm that NF-kB activation is impaired in EDA and support the role of EDARADD DD as a downstream effector of EDAR signaling.

Research paper thumbnail of Autisme, génétique et anomalies de la fonction synaptique

Pathologie Biologie, Oct 1, 2010

Autism is a neurodevelopmental disorder characterized by a deficit of language and communication ... more Autism is a neurodevelopmental disorder characterized by a deficit of language and communication both associated with a restricted repertoire of activities and interests. The current prevalence of autistic disorder stricto sensu is estimated at 1/500 whereas autism spectrum disorders (ASD) increases up to 1/150 to 1/200. Mental deficiency (MD) and epilepsy are present in numerous autistic individuals. Consequently, autism is as a major public health issue. Autism was first considered as a non biological disease; however various rational approaches for analysing epidemiological data suggested the possibility of the influence of genetic factors. In 2003, this hypothesis was clearly illustrated by the characterization of genetic mutations transmitted through a mendelian manner. Subsequently, the glutamate synapse appeared as a preferential causal target in autism because the identified genes encoded proteins present in this structure. Strikingly, the findings that an identical genetic dysfunction of the synapse might also explain some MD suggested the possibility of a genetic comorbidity between these neurodevelopmental conditions. To date, various identified genes are considered indifferently as "autism" or "MD" genes. The characterization of mutations in the NLGN4X gene in patients with Asperger syndrome, autism without MD, or MD without autism, was the first example. It appears that a genetic continuum between ASD on one hand, and between autism and MD on the other hand, is present. Consequently, it is likely that genes already involved in MD will be found mutated in autistic patients and will represent future target for finding new factors in autism.

Research paper thumbnail of Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis

Nature Genetics, Mar 11, 2007

Neural progenitor proliferation and migration influence brain size during neurogenesis. We report... more Neural progenitor proliferation and migration influence brain size during neurogenesis. We report an autosomal recessive microcephaly syndrome cosegregating with a homozygous balanced translocation between chromosomes 3p and 10q, and we show that a position effect at the breakpoint on chromosome 3 silences the eomesodermin transcript (EOMES), also known as T-box-brain2 (TBR2). Together with the expression pattern of EOMES in the developing human brain, our data suggest that EOMES is involved in neuronal division and/or migration. Thus, mutations in genes encoding not only mitotic and apoptotic proteins but also transcription factors may be responsible for malformative microcephaly syndromes.

Research paper thumbnail of Implication D'Un Gene Du Spliceosome Dans Un Cas De Deficience Mentale Severe ?

Le Centre pour la Communication Scientifique Directe - HAL - Archive ouverte HAL, Feb 2, 2012

Research paper thumbnail of Claudin-1 gene mutations in neonatal sclerosing cholangitis associated with ichthyosis: A tight junction disease

Research paper thumbnail of Sensitivity and specificity of heat and moisture exchange filters sampling for SARS-CoV-2 detection in mechanically ventilated COVID-19 patients

Journal of Microbiology, Immunology and Infection

We assessed the sensitivity and specificity of SARS-CoV-2 detection by polymerase chain reaction ... more We assessed the sensitivity and specificity of SARS-CoV-2 detection by polymerase chain reaction in heat and moisture exchange filters (HMEF) in mechanically ventilated COVID-19 patients. We showed that testing HMEF might obviate the need for a tracheal sample to affirm that a patient is not ready to end isolation.

Research paper thumbnail of Autisme, génétique et anomalies de la fonction synaptique

Pathologie Biologie, 2010

Autism is a neurodevelopmental disorder characterized by a deficit of language and communication ... more Autism is a neurodevelopmental disorder characterized by a deficit of language and communication both associated with a restricted repertoire of activities and interests. The current prevalence of autistic disorder stricto sensu is estimated at 1/500 whereas autism spectrum disorders (ASD) increases up to 1/150 to 1/200. Mental deficiency (MD) and epilepsy are present in numerous autistic individuals. Consequently, autism is as a major public health issue. Autism was first considered as a non biological disease; however various rational approaches for analysing epidemiological data suggested the possibility of the influence of genetic factors. In 2003, this hypothesis was clearly illustrated by the characterization of genetic mutations transmitted through a mendelian manner. Subsequently, the glutamate synapse appeared as a preferential causal target in autism because the identified genes encoded proteins present in this structure. Strikingly, the findings that an identical genetic dysfunction of the synapse might also explain some MD suggested the possibility of a genetic comorbidity between these neurodevelopmental conditions. To date, various identified genes are considered indifferently as "autism" or "MD" genes. The characterization of mutations in the NLGN4X gene in patients with Asperger syndrome, autism without MD, or MD without autism, was the first example. It appears that a genetic continuum between ASD on one hand, and between autism and MD on the other hand, is present. Consequently, it is likely that genes already involved in MD will be found mutated in autistic patients and will represent future target for finding new factors in autism.

Research paper thumbnail of The ciliary gene RPGRIP1L is mutated in cerebello-oculo-renal syndrome (Joubert syndrome type B) and Meckel syndrome

Nature Genetics, 2007

Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) synd... more Cerebello-oculo-renal syndrome (CORS), also called Joubert syndrome type B, and Meckel (MKS) syndrome belong to the group of developmental autosomal recessive disorders that are associated with primary cilium dysfunction. Using SNP mapping, we identified missense and truncating mutations in RPGRIP1L (KIAA1005) in both CORS and MKS, and we show that inactivation of the mouse ortholog Rpgrip1l (Ftm) recapitulates the cerebral, renal and hepatic defects of CORS and MKS. In addition, we show that RPGRIP1L colocalizes at the basal body and centrosomes with the protein products of both NPHP6 and NPHP4, known genes associated with MKS, CORS and nephronophthisis (a related renal disorder and ciliopathy). In addition, the RPGRIP1L missense mutations found in CORS individuals diminishes the interaction between RPGRIP1L and nephrocystin-4. Our findings show that mutations in RPGRIP1L can cause the multiorgan phenotypic abnormalities found in CORS or MKS, which therefore represent a continuum of the same underlying disorder. Joubert syndrome is an autosomal recessive multisystem disease characterized by cerebellar ataxia, developmental delay, hypotonia, irregular breathing pattern, eye movement abnormalities 1 and cerebellar vermis hypoplasia and dysplasia with accompanying brainstem defects. When visualized on axial images using magnetic resonance imaging (MRI), the brainstem defects give rise to the 'molar tooth sign' (MTS) 2. A related disorder, CORS, is defined by the features of Joubert syndrome with the addition of one or more of the following: renal involvement (nephronophthisis or cystic renal dysplasia), retinal dystrophy, coloboma, polydactyly or liver fibrosis. Nephronophthisis (NPHP), the most common genetic cause of chronic renal failure in children, is characterized by interstitial fibrosis and medullary cyst formation. Disease-causing mutations have been identified in six genes (NPHP1-NPHP6) whose protein products are known to localize to primary cilia 3-5. Joubert syndrome is a genetically heterogeneous condition with recessive mutations in two known genes: AHI1 (ref. 6) and NPHP6 (also known as CEP290) 4,5. In addition, a homozygous NPHP1 deletion shown to be the most common cause of juvenile NPHP has been identified in a subset of individuals with NPHP and Joubert syndrome 7-9 who present with a milder form of the neurological symptoms 10. Two more loci, JBTS1 (CORS1; ref. 11) and JBTS2 (CORS2; ref. 12), have been mapped to chromosomes 9q34.3 and 11p12-11q13.3, respectively.

Research paper thumbnail of Pleiotropic Effects of CEP290 (NPHP6) Mutations Extend to Meckel Syndrome

The American Journal of Human Genetics, 2007

Research paper thumbnail of The Meckel-Gruber Syndrome Gene, MKS3, Is Mutated in Joubert Syndrome

The American Journal of Human Genetics, 2007

Research paper thumbnail of Both Recessive and Dominant Forms of Anhidrotic/Hypohidrotic Ectodermal Dysplasia Map to Chromosome 2q11-q13

The American Journal of Human Genetics, 1999

Research paper thumbnail of Moroccan family with Joubert syndrome: a

Research paper thumbnail of Cartographie par autozygotie et identification de gènes de maladies rares dans la population marocaine : application aux génodermatoses et à une anomalie de développement cérébral

Les maladies genetiques transmises selon le mode autosomique recessif constituent un veritable pr... more Les maladies genetiques transmises selon le mode autosomique recessif constituent un veritable probleme de sante publique au Maroc du fait du taux eleve de consanguinite. Tirant partie de la consanguinite, la cartographie par autozygotie permet de localiser pour les identifier les genes de ces maladies. Ces puissantes methodes nous ont permis de localiser et d'identifier les genes de trois maladies autosomiques recessives : 1) deux genodermatoses dont une forme recessive de dysplasie ectodermique anhidrotique (DEA) et un syndrome associant ichtyose et cholangite sclerosante (NISCH), et 2) un syndrome de microcephalie avec une agenesie du corps calleux, une craniostenose et un retard mental. Nos travaux ont contribue a mettre en evidence l'importance de l'analyse des maladies genetiques rares dans les populations a fort taux de consanguinite.

Research paper thumbnail of Case Report: Co-infection with SARS-CoV-2 and influenza H1N1 in a patient with acute respiratory distress syndrome

F1000Research, 2020

Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 ... more Coronavirus disease 2019 (COVID-19) is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection and has been a global public health concern. Co-infection of SARS-CoV-2 and other respiratory syndrome has been rarely reported. We report coinfection of SARS-CoV-2 and 2009 H1N1 Influenza strain in a French patient with pneumonia leading to acute respiratory distress syndrome. The patient also had a medical history of pulmonary sarcoidosis with a restrictive ventilatory syndrome, which would be a supplementary risk to develop a poor outcomes. This case highlights the possible coinfection of two severe SARS-CoV-2 and influenza H1N1 viruses, which presents a higher risk to extend the care duration. The overlapping clinical features of the two respiratory syndromes is a challenge, and awareness is required to recommend an early differential diagnosis.

Research paper thumbnail of Cartographie par autozygotie et identification de gènes de maladies rares dans la population marocaine : application aux génodermatoses et à une anomalie de développement cérébral

Research paper thumbnail of A homozygous AHI1 gene mutation (p.Thr304AsnfsX6) in a consanguineous Moroccan family with Joubert syndrome: a case report

Journal of Medical Case Reports, 2015

Introduction: Joubert syndrome is a rare congenital disorder characterized by brain malformation,... more Introduction: Joubert syndrome is a rare congenital disorder characterized by brain malformation, developmental delay with hypotonia, ocular motor apraxia, and breathing abnormalities. Joubert syndrome is a genetically highly heterogeneous ciliopathy disorder with 23 identified causative genes. The diagnosis is based on brain imaging showing the "molar tooth sign" with cerebellar vermis agenesis. We describe a consanguineous Moroccan family with three affected siblings (18-year-old boy, 13-year-old girl, and 10-year-old boy) showing typical signs of Joubert syndrome, and attempt to identify the underlying genetic defect in this family. Methods: We performed genome-wide homozygosity mapping using a high-resolution array followed by targeted Sanger sequencing to identify the causative gene. Results: This approach found three homozygous regions, one including the AHI1 gene. Direct sequencing of the 26 coding exons of AHI1 revealed a homozygous mutation (p.Thr304AsnfsX6) located in exon 7 present in the three Joubert syndrome-affected Moroccan siblings. Of more interest, this truncating mutation was previously reported in patients with compound heterozygous Joubert syndrome originating from Spain (one patient) and from the Netherlands (two patients), suggesting a possible founder effect or mutational hotspot. Conclusions: Combined homozygosity mapping and targeted sequencing allowed the rapid detection of the disease-causing mutation in the AHI1 gene in this family affected with a highly genetically heterogeneous disorder. Carriers of the same truncating mutation (p.Thr304AsnfsX6), originating from Spain and the Netherlands, presented variable clinical characteristics, thereby corroborating the extreme heterogeneity of Joubert syndrome.

Research paper thumbnail of Homozygous silencing of T-box transcription factor EOMES leads to microcephaly with polymicrogyria and corpus callosum agenesis

Nature Genetics, 2007

Neural progenitor proliferation and migration influence brain size during neurogenesis. We report... more Neural progenitor proliferation and migration influence brain size during neurogenesis. We report an autosomal recessive microcephaly syndrome cosegregating with a homozygous balanced translocation between chromosomes 3p and 10q, and we show that a position effect at the breakpoint on chromosome 3 silences the eomesodermin transcript (EOMES), also known as T-box-brain2 (TBR2). Together with the expression pattern of EOMES in the developing human brain, our data suggest that EOMES is involved in neuronal division and/or migration. Thus, mutations in genes encoding not only mitotic and apoptotic proteins but also transcription factors may be responsible for malformative microcephaly syndromes.

Research paper thumbnail of Autosomal recessive anhidrotic ectodermal dysplasia in a large Moroccan family

Journal of Medical Genetics, 1998

We studied a large Moroccan family in which anhidrotic ectodermal dysplasia is transmitted as an ... more We studied a large Moroccan family in which anhidrotic ectodermal dysplasia is transmitted as an autosomal recessive trait. Fourteen family members, both males and females, were affected and they all had a common ancestor. Linkage analysis by homozygosity mapping in this family will permit the gene localisation of this rare form of anhidrotic ectodermal dysplasia.

Research paper thumbnail of Homozygosity Mapping of a Locus for a Novel Syndromic Ichthyosis to Chromosome 3q27-q28

Journal of Investigative Dermatology, 2002

Ichthyosis is a heterogeneous group of skin disorders characterized by abnormal epidermal scaling... more Ichthyosis is a heterogeneous group of skin disorders characterized by abnormal epidermal scaling. Occasionally, extracutaneous features are associated. A novel autosomal recessive ichthyosis syndrome is described here with scalp hypotrichosis, scarring alopecia, sclerosing cholangitis, and leukocyte vacuolization in two inbred kindreds of Moroccan origin. We also report the mapping of the diseased gene to a 21.2 cM interval of chromosome 3q27-q28. Homo zygosity for polymorphic markers has enabled us to reduce the genetic interval to a 16.2 cM region. Furthermore, comparison of mutant chromosomes in the two families has suggested a common ancestral mutant haplotype. This linkage disequilibrium has reduced the genetic interval encompassing the diseased gene to less than 9.5 cM maximum. Further study of additional families from the same geographic area will hopefully reduce the genetic interval as well as help in the cloning of the gene involved in this rare disorder.

Research paper thumbnail of Spectrum of HLXB9 gene mutations in Currarino syndrome and genotype-phenotype correlation

Human Mutation, 2008

Communicated by Sergio Ottolenghi Currarino syndrome (CS) is a rare congenital malformation descr... more Communicated by Sergio Ottolenghi Currarino syndrome (CS) is a rare congenital malformation described in 1981 as the association of three main features: typical sacral malformation (sickle-shaped sacrum or total sacral agenesis below S2), hindgut anomaly, and presacral tumor. In addition to the triad, tethered cord and/or lipoma of the conus are also frequent and must be sought, as they may lead to severe complications if not treated. The HLXB9 gene, located at 7q36, is disease-causing. It encodes the HB9 transcription factor and interacts with DNA through a highly evolutionarily conserved homeodomain early in embryological development. Thus far, 43 different heterozygous mutations have been reported in patients fulfilling CS criteria. Mutation detection rate is about 50%, and reaches 90% in familial cases. Here, we report 23 novel mutations in 26 patients among a series of 50 index cases with CS, and review mutational reports published since the identification of the causative gene. Three cytogenetic anomalies encompassing the HLXB9 gene are described for the first time. Truncating mutations (frameshifts or nonsense mutations) represent 57% of those identified, suggesting that haploinsufficiency is the basis of CS. No obvious genotype-phenotype correlation can be drawn thus far. Genetic heterogeneity is suspected, since at least 19 of the 24 patients without HLXB9 gene mutation harbor subtle phenotypic variations.

Research paper thumbnail of Autosomal dominant anhidrotic ectodermal dysplasias at the EDARADD locus

Human Mutation, 2007

Communicated by Sergio Ottolenghi Anhidrotic ectodermal dysplasia (EDA) is a disorder of ectoderm... more Communicated by Sergio Ottolenghi Anhidrotic ectodermal dysplasia (EDA) is a disorder of ectodermal differentiation characterized by sparse hair, abnormal or missing teeth, and inability to sweat. X-linked EDA is the most common form, caused by mutations in the EDA gene, which encodes ectodysplasin, a member of the tumor necrosis factor (TNF) family. Autosomal dominant and recessive forms of EDA have been also described and are accounted for by two genes. Mutations in EDAR, encoding a TNF receptor (EDAR) cause both dominant and recessive forms. In addition, mutations in a recently identified gene, EDARADD, encoding EDAR-associated death domain (EDARADD) have been shown to cause autosomal recessive EDA. Here, we report a large Moroccan family with an autosomal dominant EDA. We mapped the disease gene to chromosome 1q42.2-q43, and identified a novel missense mutation in the EDARADD gene (c.335T4G, p.Leu112Arg). Thus, the EDARADD gene accounts for both recessive and dominant EDA. EDAR is activated by its ligand, ectodysplasin, and uses EDARADD to build an intracellular complex and activate nuclear factor kappa B (NF-kB). We compared the functional consequences of the dominant (p.Leu112Arg) and recessive mutation (p.Glu142Lys), which both occurred in the death domain (DD) of EDARADD. We demonstrated that the p.Leu112Arg mutation completely abrogated NF-kB activation, whereas the p.Glu142Lys retained the ability to significantly activate the NF-kB pathway. The p.Leu112Arg mutation is probably a dominant negative form as its cotransfection impaired the wild-type EDARADD's ability to activate NF-kB. Our results confirm that NF-kB activation is impaired in EDA and support the role of EDARADD DD as a downstream effector of EDAR signaling.