Latifa Hilal - Academia.edu (original) (raw)
Papers by Latifa Hilal
American Journal of Human Genetics, 1994
The generalized mutilating form of recessive dystrophic epidermolysis bullosa (i.e., the Hallopea... more The generalized mutilating form of recessive dystrophic epidermolysis bullosa (i.e., the Hallopeau-Siemens type; HS-RDEB) is a life-threatening disease characterized by extreme mucocutaneous fragility associated with absent or markedly altered anchoring fibrils (AF). Recently, the authors reported linkage between HS-RDEB and the type VII collagen gene (COL7A1), which encodes the major component of AF. In this study, they investigated 52 unrelated
American journal of human genetics, 1994
The generalized mutilating form of recessive dystrophic epidermolysis bullosa (i.e., the Hallopea... more The generalized mutilating form of recessive dystrophic epidermolysis bullosa (i.e., the Hallopeau-Siemens type; HS-RDEB) is a life-threatening disease characterized by extreme mucocutaneous fragility associated with absent or markedly altered anchoring fibrils (AF). Recently, we reported linkage between HS-RDEB and the type VII collagen gene (COL7A1), which encodes the major component of AF. In this study, we investigated 52 unrelated HS-RDEB patients and 2 patients with RDEB inversa for the presence, at CpG dinucleotides, of mutations changing CGA arginine codons to premature stop codons TGA within the COL7A1 gene. Eight exons containing 10 CGA codons located in the amino-terminal domain of the COL7A1 gene were studied. Mutation analysis was performed using denaturing gradient gel electrophoresis of PCR-amplified genomic fragments. Direct sequencing of PCR-amplified products with altered electrophoretic mobility led to the characterization of three premature stop codons, each in a...
Clinical Endocrinology, 2014
Congenital hypopituitarism is a rare disease which, for most patients, has no identified molecula... more Congenital hypopituitarism is a rare disease which, for most patients, has no identified molecular cause. We aimed to document the molecular basis of growth retardation in a Moroccan cohort. 80 index cases [54 with isolated growth hormone deficiency (IGHD), 26 with combined pituitary hormone deficiency (CPHD)] were screened for molecular defects in GH1 (including LCR-GH1), GHRHR, GHSR, GHRH, PROP1, POU1F1, HESX1, LHX3, LHX4 and SOX3. Five different deleterious mutations were identified in 14 patients from eight families. In the IGHD group, three genes were found to be involved: GH1, GHRHR and GHSR. In the CPHD group, PROP1 was the only mutated gene. In addition, two heterozygous variations whose deleterious effect remains to be demonstrated were identified (in GH1 and LHX4), and two polymorphisms (missense variations) were detected (in LHX3 and in GHSR). The prevalence of mutations in this Moroccan GHD cohort was 10% (8/80), 11·1% (6/54) in the IGHD group and 7·7% (2/26) in the CPHD group. This is the first molecular screening of congenital GHD in a Moroccan population and, like other studies, mutations were preferentially identified in familial cases (75%); mutations in genes such as POU1F1, HESX1, SOX3, LHX3 and LHX4 are extremely rare. The p.R73C PROP1 mutation was the most frequent mutation in CPHD; this should be the first one to screen in this population. Our results should contribute to a better diagnosis and management of this heterogeneous disease condition.
Molecular medicine (Cambridge, Mass.)
Isolated growth hormone deficiency (IGHD) may be of genetic origin. One of the few genes involved... more Isolated growth hormone deficiency (IGHD) may be of genetic origin. One of the few genes involved in that condition encodes the growth hormone releasing hormone receptor (GHRHR) that, through its ligand (GHRH), plays a pivotal role in the GH synthesis and secretion by the pituitary. Our objective is to describe the phenotype of two siblings born to a consanguineous union presenting with short stature (IGHD) and Magnetic Resonance Imaging (MRI) abnormalities, and to identify the molecular basis of this condition. Our main outcome measures were clinical and endocrinological investigations, MRI of the pituitary region, study of the GHRHR gene sequence and transcripts. In both patients, the severe growth retardation (-5SD) was combined with anterior pituitary hypoplasia. In addition to these classical phenotypic features for IGHD, one of the patients had a Chiari I malformation, an arachnoid cyst, and a dysmorphic anterior pituitary. A homozygous sequence variation in the consensus dono...
Bulletin du cancer, 2008
Multiple endocrine neoplasia (MEN) 2A is an inherited disease characterized by the development of... more Multiple endocrine neoplasia (MEN) 2A is an inherited disease characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma and/or hyperparathyroïdism. It has been shown to be associated with germline mutations in the RET proto-oncogene. Direct DNA testing, therefore allows the identification of subjects with asymptomatic MEN 2A who can be offered prophylactic thyroidectomy and biochemical screening as preventive measures. DNA analysis of RET exon 8, 10, 13, 14, 15 and 16 was performed by direct sequencing of PCR product on automated sequencer and or PCR-digestion. In this report, we describe a MEN2A family witch initially seemed a sporadic case of MTC. We first characterized the C634R RET mutation in the index and then we identified 3 carriers who developed the disease and 3 young carriers who were apparently asymptomatic. A genetic counselling and the management of the carriers were proposed. This study confirmed that genetic testing ; in order to detect ...
Molecular vision, 2010
To investigate the contribution of cytochrome P4501B1 (CYP1B1) and myocillin (MYOC) mutations to ... more To investigate the contribution of cytochrome P4501B1 (CYP1B1) and myocillin (MYOC) mutations to primary congenital glaucoma (PCG) in Moroccan families. This study included 90 unrelated families with PCG and 100 normal control individuals. Two previously reported CYP1B1 mutations (g.4339delG and p.G61E) were first screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The coding exons of CYP1B1 were sequenced in g.4339delG- and p.G61E-negative or heterozygous probands. Then the coding exons of MYOC were sequenced in patients who had no mutation in CYP1B1 or carried heterozygous CYP1B1 mutation. Twelve CYP1B1 mutations were identified in 43 PCG pedigrees. Three of them were novel (p.R163C, p.C470Y, and g.4330-4331delTG) and associated with moderate to severe phenotypes. Two novel intronic polymorphisms in CYP1B1 were identified in addition to those previously described. The g.4339delG was the most frequent mutation detected in 31 families (34.44%),...
Ophthalmic Genetics, 2002
Autosomal dominant cerulean cataracts (ADCC) have previously been mapped to two loci: one on chro... more Autosomal dominant cerulean cataracts (ADCC) have previously been mapped to two loci: one on chromosome 17q24 and the other on chromosome 22q11.2-q12.2, which includes the b-B2 crystallin (CRYBB2) candidate gene. Using polymorphic markers in these regions (D17S802, D17S836, D17S1806 and CRYBB2, D22S258) for linkage analysis, we excluded these loci in a large Moroccan family presenting with an unusual form of ADCC with early onset of lens opacities and rapid evolution. This finding confirms the clinical and genetic heterogeneity of autosomal dominant congenital cerulean cataracts.
Nucleic Acids Research, 1987
The steroid hormone 20-hydroxyecdysone (20-OHE) induces, in Kc cultured Drosophila melanogaster c... more The steroid hormone 20-hydroxyecdysone (20-OHE) induces, in Kc cultured Drosophila melanogaster cells, important morphological transformations and specific changes of enzymatic activities and of protein synthesis . These changes are accompanied by an increase of synthesis and an accumulation of actin. Specific probes were used to reveal transcripts of each actin gene in mRNA populations isolated from cells at various times of 20-OHE treatment. Only the two cytoplasmic actin genes 5C and 42A are expressed in Kc cells and the hormone induces the accumulation of transcripts of these two genes. We have also taken advantage of Si mapping and extension procedures to identify the 5' ends of the actin mRNAs from these two genes and to compare their respective levels of expression. The 5C gene is more expressed than the 42A one in untreated and in hormone treated cells. The 5C gene encodes three RNAs that differ in their 3' end. The two genes are interrupted by an intervening sequence immediately upstream of ATG initiation codon but not at the same position. The transcription rate for the two genes is increased up to five fold upon 20-OHE treatment, demonstrating a direct effect of the steroid hormone at the transcriptional level for these genes.
Nature Genetics, 1993
Epidermolysis bullosa simplex (EBS) is a group of epidermal blistering diseases almost invariably... more Epidermolysis bullosa simplex (EBS) is a group of epidermal blistering diseases almost invariably transmitted as a dominant trait, which has recently been shown to arise from mutations in keratins 14 and 5 (K14 and K5). We describe a family with recessive EBS in which the disease is tightly linked to the substitution of the highly conserved glutamic acid-144 to alanine in the first helical segment of the rod domain of keratin 14. In contrast, linkage with keratin 5 was excluded. The loss of an ionic interaction with keratin 5 is likely to affect K14-K5 heterodimer formation. Our data suggest that this mutation underlies EBS in our family, and that mutations in keratin genes may impair the mechanical integrity of basal keratinocytes in a recessive as well as dominant fashion.
Journal of Medical Genetics, 2003
Congenital cataracts are a major cause of bilateral visual impairment in childhood. We mapped the... more Congenital cataracts are a major cause of bilateral visual impairment in childhood. We mapped the gene responsible for autosomal congenital cerulean cataracts to chromosome 2q33-35 in a four generation family of Moroccan descent. The maximum lod score (7.19 at recombination fraction theta=0) was obtained for marker D2S2208 near the gamma-crystallin gene (CRYG) cluster. Sequencing of the coding regions of the CRYGA, B, C, and D genes showed the presence of a heterozygous C>A transversion in exon 2 of CRYGD that is associated with cataracts in this family. This mutation resulted in a proline to threonine substitution at amino acid 23 of the protein in the first of the four Greek key motifs that characterise this protein. We show that although the x ray crystallography modelling does not indicate any change of the backbone conformation, the mutation affects a region of the Greek key motif that is important for determining the topology of this protein fold. Our data suggest strongly that the proline to threonine substitution may alter the protein folding or decrease the thermodynamic stability or solubility of the protein. Furthermore, this is the first report of a mutation in this gene resulting in autosomal dominant congenital cerulean cataracts.
Journal of Investigative Dermatology, 1995
Linkage analyses in generalized recessive dystrophic epidermolysis bullosa (RDEB) have implicated... more Linkage analyses in generalized recessive dystrophic epidermolysis bullosa (RDEB) have implicated the type VII collagen gene (COL7A1), which encodes the major component of anchoring fibrils, and recent identification of COL7A1 mutations has provided direct evidence for COL7A1 defects underlying RDEB. In this study, COL7A1 gene analysis was used to successfully perform first-trimester prenatal diagnosis in six families at risk for recurrence of the disease. In four families, three affected with the most severe variant of RDEB (the Hallopeau-Siemens form, HS-RDEB) and one with generalized nonmutilating RDEB, prenatal diagnosis was established by linkage analysis using polymerase chain reaction-based detection of PvuII and AluI intragenic restriction fragment length polymorphism. In two other HS-RDEB families, prenatal diagnosis was carried out by direct detection of mutations in COL7A1, using denaturing gradient gel electrophoresis analysis of polymerase chain reaction-amplified genomic fragments. Analysis of fetal DNA from chorionic villus biopsy or from amniotic fluid cells showed that the fetus had inherited at least one normal COL7A1 allele in all cases. Therefore, the fetus was predicted to be unaffected in the six pregnancies, and this has been confirmed in the newborn infants. Genotype analysis with COL7A1 polymorphic markers, or direct COL7A1 mutation detection in families at risk for the disease, represent early and rapid diagnostic alternatives to second-trimester evaluation of fetal skin samples, and thus offer a major advance in prenatal diagnosis of this life-threatening form of epidermolysis bullosa.
Journal of Clinical Investigation, 2006
The growth hormone (GH) secretagogue receptor (GHSR) was cloned as the target of a family of synt... more The growth hormone (GH) secretagogue receptor (GHSR) was cloned as the target of a family of synthetic molecules endowed with GH release properties. As shown recently through in vitro means, this receptor displays a constitutive activity whose clinical relevance is unknown. Although pharmacological studies have demonstrated that its endogenous ligand -ghrelin -stimulates, through the GHSR, GH secretion and appetite, the physiological importance of the GHSR-dependent pathways remains an open question that gives rise to much controversy. We report the identification of a GHSR missense mutation that segregates with short stature within 2 unrelated families. This mutation, which results in decreased cell-surface expression of the receptor, selectively impairs the constitutive activity of the GHSR, while preserving its ability to respond to ghrelin. This first description, to our knowledge, of a functionally significant GHSR mutation, which unveils the critical importance of the GHSR-associated constitutive activity, discloses an unusual pathogenic mechanism of growth failure in humans.
Annales d'Endocrinologie, 2006
ABSTRACT Le cancer médullaire de la thyroïde (CMT) est un cancer qui se développe au dépens des c... more ABSTRACT Le cancer médullaire de la thyroïde (CMT) est un cancer qui se développe au dépens des cellules C d’origine neuroectodermique, sécrétant la calcitonine. Il peut être isolé ou associé à d’autres endocrinopathies dans le cadre d’une néoplasie endocrinienne multiple de type 2 (NEM 2). Les formes familiales de CMT, dont la fréquence reste sous-estimée, représentent 25 à 40 % des cas. Elles sont transmises selon le mode autosomique dominant. Des mutations germinales du proto-oncogène RET ont été décrites dans environ 98 % des NEM 2A.Bien que ce cancer soit rare, il a suscité un grand intérêt du fait de son caractère héréditaire. De plus, depuis la découverte du gène RET, un diagnostic moléculaire fiable est possible, à un stade pré-clinique voire même pré-biologique. Ce diagnostic précoce, en permettant des gestes thérapeutiques précoces, est le seul garant d’une guérison complète.Au cours de ce travail, nous avons caractérisé la première mutation du gène RET, responsable de néoplasie endocrinienne multiple de type 2A au Maroc. Il s’agit de la mutation C634Y identifiée à l’état hétérozygote chez deux patients marocains d’une même famille atteinte NEM 2A. Le dépistage familial que nous avons entamé a montré que 6 membres de cette famille, cliniquement sains, sont non porteurs de la mutation C634Y. Ainsi, nous espérons contribuer à la mise en place d’un dépistage génétique des NEM 2 et du CMT au Maroc.Medullary thyroid carcinoma (MTC) is a rare cancer which originates from the calcitonin producing “C” cells of thyroid gland. It presents in as isolated form or as part of the multiple endocrine neoplasia type 2 (MEN 2). The familial form of MTC which frequency remains underestimated, account for 25 to 40% of all MTC presentations. All hereditary forms are transmitted in an autosomal dominant manner and are due to proto-oncogene RET germ line mutations.Although MCT is relatively rare, preclinical or prebiological diagnosis can be achieved with genetic screening with high specificity and sensitivity. Early diagnosis is crucial for disease prevention.In this study we identified the first RET mutation underlying NEM 2A in Morocco. The C634Y mutation was present in the heterozygous state in a Moroccan family with MEN 2A. Genetic screening showed that six asymptomatic members of this family were not C364Y carriers. This report should contribute to the development of genetic screening for NEM 2 and F-MTC in Morocco.
biologie-sante.com
La leptine, produit du gène ob, est l'hormone clef de l'homéostasie énergétique qui contrôle la p... more La leptine, produit du gène ob, est l'hormone clef de l'homéostasie énergétique qui contrôle la prise alimentaire et permet le maintien d'un poids corporel stable. Les souris ob/ob déficientes en leptine sont massivement obèses, ainsi que les animaux porteurs de mutations sur le gène de son récepteur. Ces deux types de mutations qui affectent les concentrations circulantes de leptine existent chez l'homme, mais ne concernent à ce jour que quelques individus, massivement obèses. Dans cette étude, nous avons mesuré la leptinémie dans une population de 41 sujets marocains obèses (Indice de Masse Corporelle, IMC≥30 Kg/m 2 ) comprenant 7 hommes et 34 femmes, dans le but de détecter des individus déficients en leptine ou en son récepteur. Une population d'individus de poids normal (IMC<30 Kg/m 2 ) a également été étudiée. En accord avec les observations dans d'autres populations, la leptinémie est plus élevée chez la femme (34,8±2,5ng/ml) que chez l'homme (10,4±2,1ng/ml) et augmente chez les obèses quel que soit le sexe (12,6±2,2ng/ml chez les non obèses et 33,7±2,7ng/ml chez les obèses). Des analyses de régression ont permis d'estimer la contribution des paramètres anthropométriques dans la variabilité de la leptinémie dans cet échantillon. De ces paramètres, l'IMC s'avère le plus fortement corrélé avec la leptinémie (r = 0,56, p<0,001). Nous n'avons pas observé de déviation de la relation leptinémie/IMC dans cette population, excluant l'existence d'un défaut moléculaire dans le gène de la leptine ou de son récepteur.
Clinical Cancer Investigation Journal, 2015
American Journal of Human Genetics, 1994
The generalized mutilating form of recessive dystrophic epidermolysis bullosa (i.e., the Hallopea... more The generalized mutilating form of recessive dystrophic epidermolysis bullosa (i.e., the Hallopeau-Siemens type; HS-RDEB) is a life-threatening disease characterized by extreme mucocutaneous fragility associated with absent or markedly altered anchoring fibrils (AF). Recently, the authors reported linkage between HS-RDEB and the type VII collagen gene (COL7A1), which encodes the major component of AF. In this study, they investigated 52 unrelated
American journal of human genetics, 1994
The generalized mutilating form of recessive dystrophic epidermolysis bullosa (i.e., the Hallopea... more The generalized mutilating form of recessive dystrophic epidermolysis bullosa (i.e., the Hallopeau-Siemens type; HS-RDEB) is a life-threatening disease characterized by extreme mucocutaneous fragility associated with absent or markedly altered anchoring fibrils (AF). Recently, we reported linkage between HS-RDEB and the type VII collagen gene (COL7A1), which encodes the major component of AF. In this study, we investigated 52 unrelated HS-RDEB patients and 2 patients with RDEB inversa for the presence, at CpG dinucleotides, of mutations changing CGA arginine codons to premature stop codons TGA within the COL7A1 gene. Eight exons containing 10 CGA codons located in the amino-terminal domain of the COL7A1 gene were studied. Mutation analysis was performed using denaturing gradient gel electrophoresis of PCR-amplified genomic fragments. Direct sequencing of PCR-amplified products with altered electrophoretic mobility led to the characterization of three premature stop codons, each in a...
Clinical Endocrinology, 2014
Congenital hypopituitarism is a rare disease which, for most patients, has no identified molecula... more Congenital hypopituitarism is a rare disease which, for most patients, has no identified molecular cause. We aimed to document the molecular basis of growth retardation in a Moroccan cohort. 80 index cases [54 with isolated growth hormone deficiency (IGHD), 26 with combined pituitary hormone deficiency (CPHD)] were screened for molecular defects in GH1 (including LCR-GH1), GHRHR, GHSR, GHRH, PROP1, POU1F1, HESX1, LHX3, LHX4 and SOX3. Five different deleterious mutations were identified in 14 patients from eight families. In the IGHD group, three genes were found to be involved: GH1, GHRHR and GHSR. In the CPHD group, PROP1 was the only mutated gene. In addition, two heterozygous variations whose deleterious effect remains to be demonstrated were identified (in GH1 and LHX4), and two polymorphisms (missense variations) were detected (in LHX3 and in GHSR). The prevalence of mutations in this Moroccan GHD cohort was 10% (8/80), 11·1% (6/54) in the IGHD group and 7·7% (2/26) in the CPHD group. This is the first molecular screening of congenital GHD in a Moroccan population and, like other studies, mutations were preferentially identified in familial cases (75%); mutations in genes such as POU1F1, HESX1, SOX3, LHX3 and LHX4 are extremely rare. The p.R73C PROP1 mutation was the most frequent mutation in CPHD; this should be the first one to screen in this population. Our results should contribute to a better diagnosis and management of this heterogeneous disease condition.
Molecular medicine (Cambridge, Mass.)
Isolated growth hormone deficiency (IGHD) may be of genetic origin. One of the few genes involved... more Isolated growth hormone deficiency (IGHD) may be of genetic origin. One of the few genes involved in that condition encodes the growth hormone releasing hormone receptor (GHRHR) that, through its ligand (GHRH), plays a pivotal role in the GH synthesis and secretion by the pituitary. Our objective is to describe the phenotype of two siblings born to a consanguineous union presenting with short stature (IGHD) and Magnetic Resonance Imaging (MRI) abnormalities, and to identify the molecular basis of this condition. Our main outcome measures were clinical and endocrinological investigations, MRI of the pituitary region, study of the GHRHR gene sequence and transcripts. In both patients, the severe growth retardation (-5SD) was combined with anterior pituitary hypoplasia. In addition to these classical phenotypic features for IGHD, one of the patients had a Chiari I malformation, an arachnoid cyst, and a dysmorphic anterior pituitary. A homozygous sequence variation in the consensus dono...
Bulletin du cancer, 2008
Multiple endocrine neoplasia (MEN) 2A is an inherited disease characterized by the development of... more Multiple endocrine neoplasia (MEN) 2A is an inherited disease characterized by the development of medullary thyroid carcinoma (MTC), pheochromocytoma and/or hyperparathyroïdism. It has been shown to be associated with germline mutations in the RET proto-oncogene. Direct DNA testing, therefore allows the identification of subjects with asymptomatic MEN 2A who can be offered prophylactic thyroidectomy and biochemical screening as preventive measures. DNA analysis of RET exon 8, 10, 13, 14, 15 and 16 was performed by direct sequencing of PCR product on automated sequencer and or PCR-digestion. In this report, we describe a MEN2A family witch initially seemed a sporadic case of MTC. We first characterized the C634R RET mutation in the index and then we identified 3 carriers who developed the disease and 3 young carriers who were apparently asymptomatic. A genetic counselling and the management of the carriers were proposed. This study confirmed that genetic testing ; in order to detect ...
Molecular vision, 2010
To investigate the contribution of cytochrome P4501B1 (CYP1B1) and myocillin (MYOC) mutations to ... more To investigate the contribution of cytochrome P4501B1 (CYP1B1) and myocillin (MYOC) mutations to primary congenital glaucoma (PCG) in Moroccan families. This study included 90 unrelated families with PCG and 100 normal control individuals. Two previously reported CYP1B1 mutations (g.4339delG and p.G61E) were first screened by polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). The coding exons of CYP1B1 were sequenced in g.4339delG- and p.G61E-negative or heterozygous probands. Then the coding exons of MYOC were sequenced in patients who had no mutation in CYP1B1 or carried heterozygous CYP1B1 mutation. Twelve CYP1B1 mutations were identified in 43 PCG pedigrees. Three of them were novel (p.R163C, p.C470Y, and g.4330-4331delTG) and associated with moderate to severe phenotypes. Two novel intronic polymorphisms in CYP1B1 were identified in addition to those previously described. The g.4339delG was the most frequent mutation detected in 31 families (34.44%),...
Ophthalmic Genetics, 2002
Autosomal dominant cerulean cataracts (ADCC) have previously been mapped to two loci: one on chro... more Autosomal dominant cerulean cataracts (ADCC) have previously been mapped to two loci: one on chromosome 17q24 and the other on chromosome 22q11.2-q12.2, which includes the b-B2 crystallin (CRYBB2) candidate gene. Using polymorphic markers in these regions (D17S802, D17S836, D17S1806 and CRYBB2, D22S258) for linkage analysis, we excluded these loci in a large Moroccan family presenting with an unusual form of ADCC with early onset of lens opacities and rapid evolution. This finding confirms the clinical and genetic heterogeneity of autosomal dominant congenital cerulean cataracts.
Nucleic Acids Research, 1987
The steroid hormone 20-hydroxyecdysone (20-OHE) induces, in Kc cultured Drosophila melanogaster c... more The steroid hormone 20-hydroxyecdysone (20-OHE) induces, in Kc cultured Drosophila melanogaster cells, important morphological transformations and specific changes of enzymatic activities and of protein synthesis . These changes are accompanied by an increase of synthesis and an accumulation of actin. Specific probes were used to reveal transcripts of each actin gene in mRNA populations isolated from cells at various times of 20-OHE treatment. Only the two cytoplasmic actin genes 5C and 42A are expressed in Kc cells and the hormone induces the accumulation of transcripts of these two genes. We have also taken advantage of Si mapping and extension procedures to identify the 5' ends of the actin mRNAs from these two genes and to compare their respective levels of expression. The 5C gene is more expressed than the 42A one in untreated and in hormone treated cells. The 5C gene encodes three RNAs that differ in their 3' end. The two genes are interrupted by an intervening sequence immediately upstream of ATG initiation codon but not at the same position. The transcription rate for the two genes is increased up to five fold upon 20-OHE treatment, demonstrating a direct effect of the steroid hormone at the transcriptional level for these genes.
Nature Genetics, 1993
Epidermolysis bullosa simplex (EBS) is a group of epidermal blistering diseases almost invariably... more Epidermolysis bullosa simplex (EBS) is a group of epidermal blistering diseases almost invariably transmitted as a dominant trait, which has recently been shown to arise from mutations in keratins 14 and 5 (K14 and K5). We describe a family with recessive EBS in which the disease is tightly linked to the substitution of the highly conserved glutamic acid-144 to alanine in the first helical segment of the rod domain of keratin 14. In contrast, linkage with keratin 5 was excluded. The loss of an ionic interaction with keratin 5 is likely to affect K14-K5 heterodimer formation. Our data suggest that this mutation underlies EBS in our family, and that mutations in keratin genes may impair the mechanical integrity of basal keratinocytes in a recessive as well as dominant fashion.
Journal of Medical Genetics, 2003
Congenital cataracts are a major cause of bilateral visual impairment in childhood. We mapped the... more Congenital cataracts are a major cause of bilateral visual impairment in childhood. We mapped the gene responsible for autosomal congenital cerulean cataracts to chromosome 2q33-35 in a four generation family of Moroccan descent. The maximum lod score (7.19 at recombination fraction theta=0) was obtained for marker D2S2208 near the gamma-crystallin gene (CRYG) cluster. Sequencing of the coding regions of the CRYGA, B, C, and D genes showed the presence of a heterozygous C>A transversion in exon 2 of CRYGD that is associated with cataracts in this family. This mutation resulted in a proline to threonine substitution at amino acid 23 of the protein in the first of the four Greek key motifs that characterise this protein. We show that although the x ray crystallography modelling does not indicate any change of the backbone conformation, the mutation affects a region of the Greek key motif that is important for determining the topology of this protein fold. Our data suggest strongly that the proline to threonine substitution may alter the protein folding or decrease the thermodynamic stability or solubility of the protein. Furthermore, this is the first report of a mutation in this gene resulting in autosomal dominant congenital cerulean cataracts.
Journal of Investigative Dermatology, 1995
Linkage analyses in generalized recessive dystrophic epidermolysis bullosa (RDEB) have implicated... more Linkage analyses in generalized recessive dystrophic epidermolysis bullosa (RDEB) have implicated the type VII collagen gene (COL7A1), which encodes the major component of anchoring fibrils, and recent identification of COL7A1 mutations has provided direct evidence for COL7A1 defects underlying RDEB. In this study, COL7A1 gene analysis was used to successfully perform first-trimester prenatal diagnosis in six families at risk for recurrence of the disease. In four families, three affected with the most severe variant of RDEB (the Hallopeau-Siemens form, HS-RDEB) and one with generalized nonmutilating RDEB, prenatal diagnosis was established by linkage analysis using polymerase chain reaction-based detection of PvuII and AluI intragenic restriction fragment length polymorphism. In two other HS-RDEB families, prenatal diagnosis was carried out by direct detection of mutations in COL7A1, using denaturing gradient gel electrophoresis analysis of polymerase chain reaction-amplified genomic fragments. Analysis of fetal DNA from chorionic villus biopsy or from amniotic fluid cells showed that the fetus had inherited at least one normal COL7A1 allele in all cases. Therefore, the fetus was predicted to be unaffected in the six pregnancies, and this has been confirmed in the newborn infants. Genotype analysis with COL7A1 polymorphic markers, or direct COL7A1 mutation detection in families at risk for the disease, represent early and rapid diagnostic alternatives to second-trimester evaluation of fetal skin samples, and thus offer a major advance in prenatal diagnosis of this life-threatening form of epidermolysis bullosa.
Journal of Clinical Investigation, 2006
The growth hormone (GH) secretagogue receptor (GHSR) was cloned as the target of a family of synt... more The growth hormone (GH) secretagogue receptor (GHSR) was cloned as the target of a family of synthetic molecules endowed with GH release properties. As shown recently through in vitro means, this receptor displays a constitutive activity whose clinical relevance is unknown. Although pharmacological studies have demonstrated that its endogenous ligand -ghrelin -stimulates, through the GHSR, GH secretion and appetite, the physiological importance of the GHSR-dependent pathways remains an open question that gives rise to much controversy. We report the identification of a GHSR missense mutation that segregates with short stature within 2 unrelated families. This mutation, which results in decreased cell-surface expression of the receptor, selectively impairs the constitutive activity of the GHSR, while preserving its ability to respond to ghrelin. This first description, to our knowledge, of a functionally significant GHSR mutation, which unveils the critical importance of the GHSR-associated constitutive activity, discloses an unusual pathogenic mechanism of growth failure in humans.
Annales d'Endocrinologie, 2006
ABSTRACT Le cancer médullaire de la thyroïde (CMT) est un cancer qui se développe au dépens des c... more ABSTRACT Le cancer médullaire de la thyroïde (CMT) est un cancer qui se développe au dépens des cellules C d’origine neuroectodermique, sécrétant la calcitonine. Il peut être isolé ou associé à d’autres endocrinopathies dans le cadre d’une néoplasie endocrinienne multiple de type 2 (NEM 2). Les formes familiales de CMT, dont la fréquence reste sous-estimée, représentent 25 à 40 % des cas. Elles sont transmises selon le mode autosomique dominant. Des mutations germinales du proto-oncogène RET ont été décrites dans environ 98 % des NEM 2A.Bien que ce cancer soit rare, il a suscité un grand intérêt du fait de son caractère héréditaire. De plus, depuis la découverte du gène RET, un diagnostic moléculaire fiable est possible, à un stade pré-clinique voire même pré-biologique. Ce diagnostic précoce, en permettant des gestes thérapeutiques précoces, est le seul garant d’une guérison complète.Au cours de ce travail, nous avons caractérisé la première mutation du gène RET, responsable de néoplasie endocrinienne multiple de type 2A au Maroc. Il s’agit de la mutation C634Y identifiée à l’état hétérozygote chez deux patients marocains d’une même famille atteinte NEM 2A. Le dépistage familial que nous avons entamé a montré que 6 membres de cette famille, cliniquement sains, sont non porteurs de la mutation C634Y. Ainsi, nous espérons contribuer à la mise en place d’un dépistage génétique des NEM 2 et du CMT au Maroc.Medullary thyroid carcinoma (MTC) is a rare cancer which originates from the calcitonin producing “C” cells of thyroid gland. It presents in as isolated form or as part of the multiple endocrine neoplasia type 2 (MEN 2). The familial form of MTC which frequency remains underestimated, account for 25 to 40% of all MTC presentations. All hereditary forms are transmitted in an autosomal dominant manner and are due to proto-oncogene RET germ line mutations.Although MCT is relatively rare, preclinical or prebiological diagnosis can be achieved with genetic screening with high specificity and sensitivity. Early diagnosis is crucial for disease prevention.In this study we identified the first RET mutation underlying NEM 2A in Morocco. The C634Y mutation was present in the heterozygous state in a Moroccan family with MEN 2A. Genetic screening showed that six asymptomatic members of this family were not C364Y carriers. This report should contribute to the development of genetic screening for NEM 2 and F-MTC in Morocco.
biologie-sante.com
La leptine, produit du gène ob, est l'hormone clef de l'homéostasie énergétique qui contrôle la p... more La leptine, produit du gène ob, est l'hormone clef de l'homéostasie énergétique qui contrôle la prise alimentaire et permet le maintien d'un poids corporel stable. Les souris ob/ob déficientes en leptine sont massivement obèses, ainsi que les animaux porteurs de mutations sur le gène de son récepteur. Ces deux types de mutations qui affectent les concentrations circulantes de leptine existent chez l'homme, mais ne concernent à ce jour que quelques individus, massivement obèses. Dans cette étude, nous avons mesuré la leptinémie dans une population de 41 sujets marocains obèses (Indice de Masse Corporelle, IMC≥30 Kg/m 2 ) comprenant 7 hommes et 34 femmes, dans le but de détecter des individus déficients en leptine ou en son récepteur. Une population d'individus de poids normal (IMC<30 Kg/m 2 ) a également été étudiée. En accord avec les observations dans d'autres populations, la leptinémie est plus élevée chez la femme (34,8±2,5ng/ml) que chez l'homme (10,4±2,1ng/ml) et augmente chez les obèses quel que soit le sexe (12,6±2,2ng/ml chez les non obèses et 33,7±2,7ng/ml chez les obèses). Des analyses de régression ont permis d'estimer la contribution des paramètres anthropométriques dans la variabilité de la leptinémie dans cet échantillon. De ces paramètres, l'IMC s'avère le plus fortement corrélé avec la leptinémie (r = 0,56, p<0,001). Nous n'avons pas observé de déviation de la relation leptinémie/IMC dans cette population, excluant l'existence d'un défaut moléculaire dans le gène de la leptine ou de son récepteur.
Clinical Cancer Investigation Journal, 2015