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1.
Nat Commun ; 12(1): 6187, 2021 10 26.
Article in English | MEDLINE | ID: mdl-34702855

ABSTRACT

Attention-deficit hyperactivity disorder (ADHD) is a common childhood-onset psychiatric disorder characterized by inattention, impulsivity and hyperactivity. ADHD exhibits substantial heritability, with rare monogenic variants contributing to its pathogenesis. Here we demonstrate familial ADHD caused by a missense mutation in CDH2, which encodes the adhesion protein N-cadherin, known to play a significant role in synaptogenesis; the mutation affects maturation of the protein. In line with the human phenotype, CRISPR/Cas9-mutated knock-in mice harboring the human mutation in the mouse ortholog recapitulated core behavioral features of hyperactivity. Symptoms were modified by methylphenidate, the most commonly prescribed therapeutic for ADHD. The mutated mice exhibited impaired presynaptic vesicle clustering, attenuated evoked transmitter release and decreased spontaneous release. Specific downstream molecular pathways were affected in both the ventral midbrain and prefrontal cortex, with reduced tyrosine hydroxylase expression and dopamine levels. We thus delineate roles for CDH2-related pathways in the pathophysiology of ADHD.


Subject(s)
Antigens, CD/genetics , Antigens, CD/metabolism , Attention Deficit Disorder with Hyperactivity/genetics , Attention Deficit Disorder with Hyperactivity/physiopathology , Cadherins/genetics , Cadherins/metabolism , Animals , Antigens, CD/chemistry , Attention Deficit Disorder with Hyperactivity/drug therapy , Attention Deficit Disorder with Hyperactivity/metabolism , Cadherins/chemistry , Child , Dopamine/metabolism , Gene Expression Profiling , Homozygote , Humans , Locomotion/drug effects , Male , Methylphenidate/therapeutic use , Mice , Mutation , Neurons/metabolism , Prefrontal Cortex/metabolism , Protein Conformation , Siblings , Synaptic Transmission/drug effects , Synaptic Vesicles/metabolism , Tyrosine 3-Monooxygenase/metabolism
2.
Clin Genet ; 94(5): 473-479, 2018 11.
Article in English | MEDLINE | ID: mdl-30039846

ABSTRACT

Four siblings of consanguineous Bedouin kindred presented at infancy with an autosomal recessive syndrome of congenital microcephaly, facial dysmorphism, strabismus, developmental delay and ataxia with positive pyramidal signs. Toward the end of their first decade, they developed areflexia, multiple cranial neuropathies and severe polyneuropathy with progressive muscle weakness, affecting proximal and distal extremities. Physical assessment exhibited kyphoscoliosis, bilateral syndactyly and distal muscle wasting with drop-foot and pes cavus. Magnetic resonance imaging (MRI) showed profound cerebellar atrophy with highly unique findings at the pontine and mesencephalic levels, previously described as "fork and bracket" signs. Genome-wide linkage analysis identified a single ~1.5 Mbp disease-associated locus on chromosome 22q13.33. Whole exome sequencing identified a single novel homozygous deleterious splice-site mutation within this locus in SET binding factor 1 (SBF1). SBF1 missense mutations were shown to underlie Charcot-Marie-Tooth (CMT) type 4B3 disease, a rare autosomal recessive subtype of CMT4. The novel SBF1 null mutation highlights distinct severe phenotypic manifestations, broadening the clinical spectrum of SBF1-related neuropathies: cerebellar and pyramidal signs evident in the first months of life with peripheral polyneuropathy emerging only toward the end of the first decade, together with unique MRI findings.


Subject(s)
Charcot-Marie-Tooth Disease/diagnosis , Charcot-Marie-Tooth Disease/genetics , Genetic Predisposition to Disease , Intracellular Signaling Peptides and Proteins/genetics , Mutation , Phenotype , RNA Splice Sites , Alleles , Brain/abnormalities , Brain/diagnostic imaging , Chromosome Mapping , Computational Biology/methods , Databases, Genetic , Female , Genetic Association Studies , Genetic Linkage , Genome-Wide Association Study , Humans , Magnetic Resonance Imaging , Male , Pedigree , Polymorphism, Single Nucleotide , Siblings , Exome Sequencing
3.
Heredity (Edinb) ; 112(2): 182-9, 2014 Feb.
Article in English | MEDLINE | ID: mdl-24084643

ABSTRACT

The Bedouin Israeli population is highly inbred and structured with a very high prevalence of recessive diseases. Many studies in the past two decades focused on linkage analysis in large, multiple consanguineous pedigrees of this population. The advent of high-throughput technologies motivated researchers to search for rare variants shared between smaller pedigrees, integrating data from clinically similar yet seemingly non-related sporadic cases. However, such analyses are challenging because, without pedigree data, there is no prior knowledge regarding possible relatedness between the sporadic cases. Here, we describe models and techniques for the study of relationships between pedigrees and use them for the inference of tribal co-ancestry, delineating the complex social interactions between different tribes in the Negev Bedouins of southern Israel. Through our analysis, we differentiate between tribes that share many yet small genomic segments because of co-ancestry versus tribes that share larger segments because of recent admixture. The emergent pattern is well correlated with the prevalence of rare mutations in the different tribes. Tribes that do not intermarry, mostly because of social restrictions, hold private mutations, whereas tribes that do intermarry demonstrate a genetic flow of mutations between them. Thus, social structure within an inbred community can be delineated through genomic data, with implications to genetic counseling and genetic mapping.


Subject(s)
Consanguinity , Population Groups/genetics , Founder Effect , Genetics, Population , Heterozygote , High-Throughput Nucleotide Sequencing , Humans , Mutation , Prevalence
4.
Mol Genet Metab ; 82(2): 167-72, 2004 Jun.
Article in English | MEDLINE | ID: mdl-15172005

ABSTRACT

Four members of an extended consanguineous Bedouin family presented with different phenotypic variants of an autosomal recessive lysosomal free sialic acid storage disease. One affected individual had congenital ascites followed by rapid clinical deterioration and death, a presentation concordant with the clinical course of infantile free sialic acid storage disorder. His three first cousins had a more slowly progressive neurodegenerative disease, in line with the clinical phenotype of the milder form (Salla type) of this lysosomal disorder. Diagnosis of free sialic acid storage disease was based on clinical findings, histology, and biochemical assays of sialic acid. Molecular studies showed that all four affected individuals were homozygous for the same novel 983G > A mutation in exon 8 of the SLC17A5 gene, replacing glycine with glutamic acid at position 328 of the sialin protein. This family demonstrates the significant phenotypic variability of the disease in affected members of a single inbred kindred with precisely the same mutation, suggesting a role for modifier genes or environmental factors. It also highlights the need to consider this rare disorder in the differential diagnosis of congenital ascites and of unexplained psychomotor retardation, ataxia, and hypomyelination in infancy.


Subject(s)
Arabs/genetics , Consanguinity , Mutation/genetics , Organic Anion Transporters/genetics , Sialic Acid Storage Disease/genetics , Sialic Acid Storage Disease/physiopathology , Symporters/genetics , Adult , Base Sequence , Child, Preschool , Female , Genetic Markers/genetics , Humans , Infant , Male , N-Acetylneuraminic Acid/analysis , Phenotype , Polymorphism, Genetic/genetics , Sialic Acid Storage Disease/diagnosis
5.
J Inherit Metab Dis ; 27(2): 267-73, 2004.
Article in English | MEDLINE | ID: mdl-15159657

ABSTRACT

Carnitine-acylcarnitine translocase CACT deficiency is a very rare autosomal recessive disease. The neonatal phenotype of CACT deficiency is characterized by hypoketotic hypoglycaemia, hyperammonaemia, cardiomyopathy and skeletal muscle weakness culminating in early death. The disease is caused by mutations in the CACT gene, which encodes a protein transporting long-chain fatty acid carnitine esters into the mitochondrial matrix. In this report, we describe the first case of CACT deficiency in the Bedouin population in Israel. The patient, the first son of consanguineous parents, was born at term after uneventful delivery. During the second day of life, he developed clinical signs of an acute metabolic crisis with severe hypoglycaemia and hyperammonaemia. Biochemical investigation suggested the diagnosis of CACT deficiency. Genetic molecular analysis confirmed this diagnosis by demonstrating that the affected child was homozygous for a novel missense mutation 793A>G, substituting glutamine by arginine (Q238R) in exon 7 of the CACT gene. Despite medical treatment and adequate nutrition, the patient died at 6 months of age.


Subject(s)
Arabs/genetics , Carnitine Acyltransferases/genetics , Carnitine/analogs & derivatives , Metabolism, Inborn Errors/genetics , Mutation, Missense , Carnitine/metabolism , Carnitine Acyltransferases/deficiency , Carnitine Acyltransferases/metabolism , Fatal Outcome , Humans , Infant, Newborn , Israel , Male , Metabolism, Inborn Errors/metabolism , Oxidation-Reduction
6.
Mech Dev ; 96(2): 223-7, 2000 Sep.
Article in English | MEDLINE | ID: mdl-10960788

ABSTRACT

Mfge8 (milk fat globule-EGF-factor 8) encodes a soluble integrin-binding protein containing two Notch-like EGF domains and two discoidin domains. It mediates cell-to-cell interaction by binding to integrin alphavbeta3 via the RGD motif of its second EGF domain. Mfge8 was first expressed at 10.0 dpc in cells of the coelomic epithelium covering the mesonephros, and at 10.5 dpc Mfge8-expressing cells were found in the mesenchyme underneath the coelomic epithelium of the genital ridges. At 11.5-12.5 dpc, Mfge8 expressing cells were found in the stromal tissues subjacent to the coelomic epithelium that envelop the fetal gonad of both sexes. MFG-E8 protein was accumulated extracellularly in the interstitial tissues at the boundary of the mesonephros and the genital ridges. A comparison of the expression domains of Mfge8 and several gene markers showed that Mfge8 expression did not significantly overlap with the expression domain of Wt1 or Emx2, but partially with that of Lhx9 in 11.5-day XY gonads. Comparison of the expression pattern of Mfge8 with that of Hsd3beta1 in the 12.5-day testes revealed that the Mfge8-positive cells constitute a previously uncharacterized somatic cell type which is distinct from Sertoli cells, Leydig cells, peritubular myoid cells and the endothelial cells.


Subject(s)
Antigens, Surface , Membrane Glycoproteins/metabolism , Milk Proteins , Testis/cytology , Testis/embryology , Animals , Base Sequence , Carrier Proteins/genetics , Carrier Proteins/metabolism , DNA Primers/genetics , Female , Gene Expression Regulation, Developmental , Immunohistochemistry , In Situ Hybridization , Integrins/metabolism , Male , Membrane Glycoproteins/genetics , Mice , Ovary/cytology , Ovary/embryology , Ovary/metabolism , Stromal Cells/cytology , Stromal Cells/metabolism , Testis/metabolism
7.
Nature ; 403(6772): 909-13, 2000 Feb 24.
Article in English | MEDLINE | ID: mdl-10706291

ABSTRACT

During mammalian embryonic development, the ovaries and testes develop from somatic cells of the urogenital ridges as indifferent gonads, harbouring primordial germ cells that have migrated there. After sex determination of the gonads, the testes produce testosterone and anti-Mullerian hormone which mediate male sexual differentiation, and the female developmental pathway ensues in their absence. Here we show that transcripts of the LIM homeobox gene Lhx9 are present in urogenital ridges of mice at embryonic day 9.5; later they localize to the interstitial region as morphological differentiation occurs. In mice lacking Lhx9 function, germ cells migrate normally, but somatic cells of the genital ridge fail to proliferate and a discrete gonad fails to form. In the absence of testosterone and anti-Mullerian hormone, genetically male mice are phenotypically female. The expression of steroidogenic factor 1 (Sf1), a nuclear receptor essential for gonadogenesis, is reduced to minimal levels in the Lhx9-deficient genital ridge, indicating that Lhx9 may lie upstream of Sf1 in a developmental cascade. Unlike mice lacking other genes that mediate early stages of gonadogenesis, Lhx9 mutants do not exhibit additional major developmental defects. Thus, LHX9 mutations may underlie certain forms of isolated gonadal agenesis in humans.


Subject(s)
Genes, Homeobox , Gonads/embryology , Homeodomain Proteins/genetics , Animals , Chromosome Mapping , Female , Gene Deletion , Gonadal Dysgenesis/genetics , Gonads/abnormalities , LIM-Homeodomain Proteins , Male , Mice , Mice, Inbred C57BL , Sex Determination Processes , Sex Differentiation/genetics , Steroidogenic Factor 1 , Testis/embryology , Transcription Factors/genetics , Transcription Factors/physiology
8.
Proc Natl Acad Sci U S A ; 96(9): 5159-63, 1999 Apr 27.
Article in English | MEDLINE | ID: mdl-10220435

ABSTRACT

Allograft rejection is a process of immune reactivity triggered by foreign transplantation antigens. We now demonstrate that the 60-kDa heat shock protein (hsp60), a molecule that is identical in the donor and the recipient, can regulate allograft immunity. In wild-type mice, hsp60 expression was greatly enhanced in allografts being rejected. By using MHC class II (Ealpha) promoter hsp60 transgenic mice either as donors of skin with enhanced expression of hsp60, or as allograft recipients with decreased hsp60 autoimmunity, we found that augmented expression of mouse hsp60 in the allograft accelerated its rejection, whereas reduced autoimmunity to mouse hsp60 in graft recipients delayed the process. Moreover, in nontransgenic mice, therapeutic administration of hsp60 or hsp60 peptides, known to modulate naturally occurring hsp60 autoimmunity, led to delayed allograft rejection. Thus, we demonstrate that hsp60 expression and hsp60 autoimmunity can influence and modify the immune response to foreign antigens. Hence, autoimmunity to self-hsp60 epitopes is not necessarily an aberration, but may serve physiologically and therapeutically to modulate foreign immunity.


Subject(s)
Chaperonin 60/biosynthesis , Graft Rejection/metabolism , Skin Transplantation , Animals , Autoimmunity , Chaperonin 60/immunology , Chaperonin 60/pharmacology , Graft Rejection/immunology , Mice , Mice, Transgenic , Transplantation, Homologous
9.
Diabetes ; 46(5): 758-64, 1997 May.
Article in English | MEDLINE | ID: mdl-9133541

ABSTRACT

A peptide of the human 60-kDa heat-shock protein (hsp60), designated p277, was found to be useful as a therapeutic agent to arrest the autoimmune process responsible for diabetes in nonobese diabetic (NOD) mice. The effectiveness of peptide treatment was associated with the induction of peptide-specific antibodies of the IgG1 but not of the IgG2a isotype, suggesting the possibility that a Th2-type response may have been induced. We now report that the effectiveness of p277 treatment is associated with the transient activation of anti-p277 splenic T-cells that produce the Th2 cytokines interleukin-4 (IL-4) and IL-10. The Th2 response to p277 was associated with reduced Th1-type autoimmunity to hsp60 and to two other target antigens associated with diabetes: GAD and insulin. The Th2 shift appeared to be relatively specific; spontaneous T-cell reactivity to a bacterial antigen peptide remained in the Th1 mode in the p277-treated mice. Moreover, treatment with the bacterial peptide did not induce a change in cytokine profile, and it did not affect progression of the disease. Thus, effective peptide treatment of the diabetogenic process associated with the induction of antibodies may be explained by selective and transient activation of Th2 autoimmune reactivity.


Subject(s)
Antigens/immunology , Cytokines/physiology , Diabetes Mellitus, Type 1/prevention & control , Heat-Shock Proteins/therapeutic use , Hypoglycemic Agents/therapeutic use , Islets of Langerhans/immunology , Peptide Fragments/therapeutic use , Th2 Cells/metabolism , Animals , Antibody Specificity , Autoantibodies/drug effects , Autoimmunity , Chaperonin 60 , Cytokines/drug effects , Down-Regulation/drug effects , Female , Humans , Lymphocyte Activation/drug effects , Mice , Mice, Inbred NOD , T-Lymphocytes/immunology
10.
J Autoimmun ; 9(2): 159-66, 1996 Apr.
Article in English | MEDLINE | ID: mdl-8738959

ABSTRACT

In the NOD mouse, the onset of beta-cell destruction is associated with spontaneous development of T-lymphocytes reactive to members of the 60 kDa heat shock protein (hsp60) family, including the Mycobacterial (MT) and the human (H) hsp60 molecules. Diabetes in the NOD mouse is a spontaneous tissue-specific autoimmune disease occurring without prior immunization. Therefore, it has been suggested that the anti-hsp60 T cells involved in the autoimmune diabetes of NOD mice might reflect molecular mimicry between MT-hsp60 and a beta-cell tissue specific molecule sharing similar T cell epitopes, the p277 peptide of hsp60 in particular. We cloned and expressed the mouse hsp60 cDNA from a beta-cell tumour. This mouse beta-cell hsp60 cDNA was found to be identical in sequence to the hsp60 of mouse fibroblasts. We further report that NOD spleen cells and an NOD diabetogenic T cell clone C9 responded to the recombinant mouse hsp60 and to its peptide M-p277 to the same extent as to H-hsp60 and H-p277. Splenocytes of mice of other strains did not respond to p277. Moreover, treatment of 3 month old NOD mice with the non-modified self M-p277 peptide was as efficient as H-p277, from which it differs in one amino acid, in halting progression of the disease. Thus, anti-H-p277 T cells modulating diabetes in the NOD mouse are autoreactive, and are targeted at the mouse beta-cell hsp60, which is not tissue specific. These findings raise the question of how a non-tissue specific molecule may be a target of a tissue-specific autoimmune disease.


Subject(s)
Autoimmunity/immunology , Chaperonin 60/immunology , Diabetes Mellitus, Type 1/immunology , Islets of Langerhans/immunology , T-Lymphocytes/immunology , Amino Acid Sequence , Animals , Antigens/immunology , Blotting, Western , Cell Division , Chaperonin 60/genetics , Cloning, Molecular , Female , Heat-Shock Proteins/immunology , Heat-Shock Proteins/therapeutic use , Mice , Mice, Inbred BALB C , Mice, Inbred C57BL , Mice, Inbred NOD , Molecular Sequence Data , Peptide Fragments/immunology , Peptide Fragments/therapeutic use , Rabbits
11.
Proc Natl Acad Sci U S A ; 93(3): 1032-7, 1996 Feb 06.
Article in English | MEDLINE | ID: mdl-8577709

ABSTRACT

A pathogenic role for self-reactive cells against the stress protein Hsp60 has been proposed as one of the events leading to autoimmune destruction of pancreatic beta cells in the diabetes of nonobese diabetic (NOD) mice. To examine this hypothesis, we generated transgenic NOD mice carrying a murine Hsp60 transgene driven by the H-2E alpha class II promoter. This would be expected to direct expression of the transgene to antigen-presenting cells including those in the thymus and so induce immunological tolerance by deletion. Detailed analysis of Hsp60 expression revealed that the endogenous gene is itself expressed strongly in thymic medullary epithelium (and weakly in cortex) yet fails to induce tolerance. Transgenic mice with retargeted Hsp60 showed overexpression of the gene in thymic cortical epithelium and in bone marrow-derived cells. Analysis of spontaneous T-cell responses to a panel of self and heterologous Hsp60 antigens showed that tolerance to the protein had not been induced, although responses to an immunodominant 437-460 epitope implicated in disease were suppressed, probably indicating an epitope shift. This correlated with changes in disease susceptibility: insulitis in transgenic mice was substantially reduced so that pathology rarely progressed beyond periislet infiltration. This was reflected in a substantial reduction in hyperglycemia and disease. These data indicate that T cells specific for some epitopes of murine Hsp60 are likely to be involved in the islet-cell destruction that occurs in NOD mice.


Subject(s)
Chaperonin 60/biosynthesis , Chaperonin 60/immunology , Diabetes Mellitus, Type 1/immunology , Islets of Langerhans/immunology , Lymphocyte Activation , T-Lymphocytes/immunology , Animals , Diabetes Mellitus, Type 1/genetics , Disease Susceptibility , Female , Genes, MHC Class II , Immunity, Cellular , Male , Mice , Mice, Inbred C57BL , Mice, Inbred CBA , Mice, Inbred NOD , Mice, Transgenic , Polymerase Chain Reaction , Promoter Regions, Genetic , Recombinant Proteins/biosynthesis , Recombinant Proteins/immunology , Thymus Gland/immunology
12.
Curr Opin Immunol ; 5(6): 903-9, 1993 Dec.
Article in English | MEDLINE | ID: mdl-8297523

ABSTRACT

Insulin dependent diabetes mellitus is a T-cell mediated autoimmune disease. Several beta-cell antigens, mostly non-tissue-specific, have been implicated in the disease process. The antigens and the autoimmune T cells exist in healthy individuals, as do many of the genes required for the development of diabetes. The question, then, is why and how exposure to undefined environmental agents activates an existing autoimmune potential and directs it to damage the beta cells.


Subject(s)
Autoimmunity/immunology , Diabetes Mellitus, Type 1/immunology , T-Lymphocytes/immunology , Animals , Autoantigens/immunology , Diabetes Mellitus, Type 1/prevention & control , Humans , Major Histocompatibility Complex , Mice , Mice, Inbred NOD , Rats , Rats, Inbred BB
13.
Proc Natl Acad Sci U S A ; 88(8): 3088-91, 1991 Apr 15.
Article in English | MEDLINE | ID: mdl-1707531

ABSTRACT

Insulin-dependent diabetes mellitus is caused by autoimmune destruction of the insulin-producing beta cells resident in the pancreatic islets. We recently discovered that the pathogenesis of diabetes in NOD strain mice was associated with T-cell reactivity to an antigen cross-reactive with a mycobacterial 65-kDa heat shock protein. To identify peptide epitopes critical to the insulin-dependent diabetes mellitus of NOD mice, we studied the specificities of helper T-cell clones capable of causing hyperglycemia and diabetes. We now report the identification of a functionally important peptide within the sequence of the human variant of the 65-kDa heat shock protein molecule. T-cell clones recognizing this peptide mediate insulitis and hyperglycemia. Alternatively, the T cells can be attenuated and used as therapeutic T-cell vaccines to abort the diabetogenic process. Moreover, administration of the peptide itself to NOD mice can also down-regulate immunity to the 65-kDa heat shock protein and prevent the development of diabetes. Thus, T-cell vaccination and specific peptide therapy are feasible in spontaneous autoimmune diabetes.


Subject(s)
Diabetes Mellitus, Experimental/prevention & control , Diabetes Mellitus, Type 1/prevention & control , Heat-Shock Proteins/immunology , T-Lymphocytes/immunology , Animals , Autoimmune Diseases/immunology , Autoimmune Diseases/prevention & control , Clone Cells , Epitopes , Humans , Immunity, Cellular , Immunization, Passive , Lymphocyte Activation , Mice , Mice, Mutant Strains , Peptides/immunology , Vaccination
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