RESUMO
Infantile cholestatic diseases can be caused by mutations in a number of genes involved in different hepatocyte molecular pathways. Whilst some of the essential pathways have a well understood function, such as bile biosynthesis and transport, the role of the others is not known. Here we report the findings of a clinical, biochemical and molecular study of a family with three patients affected with a severe infantile cholestatic disease. A novel homozygous frameshift germline mutation (c.587delG) in the AKR1D1 gene; which encodes the enzyme Δ 4-3-oxosteroid 5ß-reductase that is required for synthesis of primary bile acids and is crucial for establishment of normal bile flow, was found in all 3 patients. Although the initial bile acid analysis was inconclusive, subsequent testing confirmed the diagnosis of a bile acid biogenesis disorder. An additional novel homozygous frameshift mutation (c.3391delC) was detected in SKIV2L in one of the patients. SKIV2L encodes a homologue of a yeast ski2 protein proposed to be involved in RNA processing and mutations in SKIV2L were recently described in patients with Tricohepatoenteric syndrome (THES). A combination of autozygosity mapping and whole-exome-sequencing allowed the identification of causal mutations in this family with a complex liver phenotype. Although the initial 2 affected cousins died in the first year of life, accurate diagnosis and management of the youngest patient led to successful treatment of the liver disease and disease-free survival.
Assuntos
DNA Helicases/genética , Mutação da Fase de Leitura , Hepatopatias/genética , Hepatopatias/fisiopatologia , Oxirredutases/genética , Índice de Gravidade de Doença , Ácidos e Sais Biliares/metabolismo , Colestase/diagnóstico , Colestase/genética , Colestase/fisiopatologia , Consanguinidade , Exoma , Feminino , Humanos , Lactente , Hepatopatias/diagnóstico , Masculino , Fenótipo , Análise de Sequência de DNARESUMO
Warburg Micro syndrome and Martsolf syndrome are heterogenous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Previously, identification of mutations in RAB3GAP1 and RAB3GAP2 in both these syndromes implicated dysregulation of the RAB3 cycle (which controls calcium-mediated exocytosis of neurotransmitters and hormones) in disease pathogenesis. RAB3GAP1 and RAB3GAP2 encode the catalytic and noncatalytic subunits of the hetrodimeric enzyme RAB3GAP (RAB3GTPase-activating protein), a key regulator of the RAB3 cycle. We performed autozygosity mapping in five consanguineous families without RAB3GAP1/2 mutations and identified loss-of-function mutations in RAB18. A c.71T > A (p.Leu24Gln) founder mutation was identified in four Pakistani families, and a homozygous exon 2 deletion (predicted to result in a frameshift) was found in the fifth family. A single family whose members were compound heterozygotes for an anti-termination mutation of the stop codon c.619T > C (p.X207QextX20) and an inframe arginine deletion c.277_279 del (p.Arg93 del) were identified after direct gene sequencing and multiplex ligation-dependent probe amplification (MLPA) of a further 58 families. Nucleotide binding assays for RAB18(Leu24Gln) and RAB18(Arg93del) showed that these mutant proteins were functionally null in that they were unable to bind guanine. The clinical features of Warburg Micro syndrome patients with RAB3GAP1 or RAB3GAP2 mutations and RAB18 mutations are indistinguishable, although the role of RAB18 in trafficking is still emerging, and it has not been linked previously to the RAB3 pathway. Knockdown of rab18 in zebrafish suggests that it might have a conserved developmental role. Our findings imply that RAB18 has a critical role in human brain and eye development and neurodegeneration.
Assuntos
Mutação , Proteínas rab de Ligação ao GTP/genética , Anormalidades Múltiplas/genética , Anormalidades Múltiplas/metabolismo , Sequência de Aminoácidos , Substituição de Aminoácidos , Sequência de Bases , Catarata/congênito , Catarata/genética , Catarata/metabolismo , Códon de Terminação , Consanguinidade , Córnea/anormalidades , Córnea/metabolismo , Análise Mutacional de DNA , Feminino , Efeito Fundador , Haplótipos , Humanos , Hipogonadismo/genética , Hipogonadismo/metabolismo , Deficiência Intelectual/genética , Deficiência Intelectual/metabolismo , Masculino , Microcefalia/genética , Microcefalia/metabolismo , Modelos Moleculares , Dados de Sequência Molecular , Proteínas Mutantes/genética , Proteínas Mutantes/metabolismo , Mutação de Sentido Incorreto , Atrofia Óptica/genética , Atrofia Óptica/metabolismo , Linhagem , Fenótipo , Ligação Proteica , Deleção de Sequência , Homologia de Sequência de Aminoácidos , Proteínas rab de Ligação ao GTP/química , Proteínas rab de Ligação ao GTP/metabolismo , Proteínas rab3 de Ligação ao GTP/genéticaRESUMO
Inherited immunodeficiency disorders can be caused by mutations in any one of a large number of genes involved in the function of immune cells. Here, we describe two families with an autosomal recessive inherited immunodeficiency disorder characterized by increased susceptibility to infection and autoimmunity. Genetic linkage studies mapped the disorder to chromosomal region 14q11.2, and a homozygous guanine-to-adenine substitution was identified at the last base of exon 3 immediately following the translational termination codon in the TCRα subunit constant gene (TRAC). RT-PCR analysis in the two affected individuals revealed impaired splicing of the mRNA, as exon 3 was lost from the TRAC transcript. The mutant TCRα chain protein was predicted to lack part of the connecting peptide domain and all of the transmembrane and cytoplasmic domains, which have a critical role in the regulation of the assembly and/or intracellular transport of TCR complexes. We found that T cells from affected individuals were profoundly impaired for surface expression of the TCRαß complex. We believe this to be the first report of a disease-causing human TRAC mutation. Although the absence of TCRαß+ T cells in the affected individuals was associated with immune dysregulation and autoimmunity, they had a surprising level of protection against infection.
Assuntos
Síndromes de Imunodeficiência/genética , Síndromes de Imunodeficiência/imunologia , Mutação , Receptores de Antígenos de Linfócitos T alfa-beta/genética , Linfócitos T/imunologia , Sequência de Bases , Pré-Escolar , Análise Mutacional de DNA , Células HeLa , Humanos , Dados de Sequência Molecular , Linhagem , Polimorfismo de Nucleotídeo Único , Receptores de Antígenos de Linfócitos T alfa-beta/metabolismo , Linfócitos T/citologiaRESUMO
The epileptic encephalopathies of infancy and childhood are a collection of epilepsy disorders characterized by refractory, severe seizures and poor neurological outcome, in which the mechanism of disease is poorly understood. We report the clinical presentation and evolution of epileptic encephalopathy in a patient, associated with a loss-of-function mutation in the phospholipase C-ß 1 gene. We ascertained a consanguineous family containing a male infant who presented with early-onset epileptic encephalopathy for detailed clinical phenotyping and molecular genetic investigation. In addition, a cohort of 12 consanguineous families of children with infantile spasms were analysed for linkage to the phospholipase C-ß 1 gene locus. The male infant presented with tonic seizures in early infancy and subsequently developed infantile spasms. Over time, he developed drug-resistant epilepsy associated with severe neurological regression and failure to thrive. Molecular genetic investigation revealed a homozygous loss-of-function 0.5-Mb deletion, encompassing the promoter element and exons 1, 2 and 3 of phospholipase C-ß 1 in the index case. Linkage to the phospholipase C-ß 1 locus was excluded in the 12 other consanguineous families, consistent with genetic heterogeneity in this disorder. Although phospholipase C-ß 1 deficiency has not previously been reported in humans, the Plcb1 homozygote knockout mouse displays early-onset severe tonic seizures and growth retardation, thus recapitulating the human phenotype. Phospholipase C-ß 1 has important functions in both hippocampal muscarinic acetylcholine receptor signalling and in cortical development. Thus, the discovery of a phospholipase C-ß 1 mutation allows us to propose a novel potential underlying mechanism in early-onset epileptic encephalopathy.
Assuntos
Epilepsia/genética , Insuficiência de Crescimento/genética , Fosfolipase C beta/genética , Eletroencefalografia , Epilepsia/fisiopatologia , Insuficiência de Crescimento/fisiopatologia , Evolução Fatal , Humanos , Lactente , Masculino , Mutação , Fenótipo , Reação em Cadeia da PolimeraseRESUMO
OBJECTIVE: Nonsyndromic autosomal recessively inherited nongoitrous congenital hypothyroidism (CHNG) can be caused by mutations in TSHR, PAX8, TSHB and NKX2-5. We aimed to investigate mutational frequencies of these genes and genotype/phenotype correlations in consanguineous families with CHNG. DESIGN: Because consanguinity in individuals with a presumptive genetic condition is often an indicator of an autosomal recessive inheritance and allows firmer correlations to be established between genotype and phenotype, we planned to execute our study in consanguineous families. PATIENTS: Hundred and thirty-nine children with CHNG phenotype born to consanguineous families. MEASUREMENTS: First, we investigated cases for evidence of linkage to the four known CHNG genes by microsatellite marker analysis. Mutation analysis by direct sequencing was then performed in those cases in whom linkage to the relevant candidate gene could not be excluded. In addition, in silico analysis of the predicted structural effects of TSHR mutations was performed and related to the mutation-specific disease phenotype. RESULTS: Homozygous germline TSHR mutations were detected in six families (5%), but no mutations were detected in PAX8, TSHB and NKX2-5. Four of TSHR mutations had not previously been described. Genotype-phenotype correlations were established and found to be related to the predicted structural effects of the mutations. CONCLUSIONS: Known causative genes account for the development of CHNG only in a minority of cases, and our cohort should provide a powerful resource to identify novel causative genes and to delineate the extent of locus heterogeneity in autosomal recessively inherited CHNG.
Assuntos
Hipotireoidismo Congênito/genética , Receptores da Tireotropina/genética , Consanguinidade , Análise Mutacional de DNA , Proteína Homeobox Nkx-2.5 , Proteínas de Homeodomínio/genética , Humanos , Modelos Moleculares , Mutação , Fator de Transcrição PAX8 , Fatores de Transcrição Box Pareados/genética , Paquistão/etnologia , Linhagem , Tireotropina Subunidade beta/genética , Fatores de Transcrição/genética , Turquia , Reino UnidoRESUMO
PURPOSE: To define the phenotype and elucidate the molecular basis for an autosomal recessively inherited optic atrophy and auditory neuropathy in a consanguineous family with two affected children. METHODS: Family members underwent detailed ophthalmologic, electrophysiological, and audiological assessments. An autozygosity mapping strategy using high-density single nucleotide polymorphism microarrays and microsatellite markers was used to detect regions of genome homozygosity that might contain the disease gene. Candidate genes were then screened for mutations by direct sequencing. RESULTS: Both affected subjects had poor vision from birth and complained of progressive visual loss over time. Current visual acuity ranged from 6/60 to 6/120. Fundus examination revealed bilateral temporal optic nerve pallor in both patients with otherwise normal retinal findings. International-standard full-field electroretinograms were normal in both individuals, with no evidence of generalized retinal dysfunction. Pattern cortical visual evoked potentials were grossly abnormal bilaterally in both cases. The pattern electroretinogram N95:P50 ratio was subnormal, and the P50 was of shortened peak time bilaterally in both patients. The electrophysiological findings were consistent with bilateral retinal ganglion cell/optic nerve dysfunction. Audiological investigation in both siblings revealed abnormalities falling within the auditory neuropathy/dysynchrony spectrum. There were no auditory symptoms and good outer hair cell function (as demonstrated by transient evoked otoacoustic emissions) but impaired inner hair cell/neural function with abnormal stapedial reflex thresholds and abnormal or absent auditory brainstem-evoked responses. The single nucleotide polymorphism microarray data demonstrated a 24.17 Mb region of homozygosity at 11q14.1-11q22.3, which was confirmed by microsatellite marker analysis. The candidate target region contained the transmembrane protein 126A (TMEM126A) gene, and direct sequencing identified a previously described nonsense mutation (c.163C>T; p.Arg55X). CONCLUSIONS: We describe the first detailed phenotyping of patients with autosomal recessive TMEM126A-associated optic atrophy and auditory neuropathy. These findings will facilitate the identification of individuals with this recently described disorder.
Assuntos
Doenças Auditivas Centrais/complicações , Doenças Auditivas Centrais/genética , Códon sem Sentido/genética , Genes Recessivos/genética , Proteínas de Membrana/genética , Atrofias Ópticas Hereditárias/complicações , Atrofias Ópticas Hereditárias/genética , Adolescente , Audiometria de Tons Puros , Doenças Auditivas Centrais/fisiopatologia , Limiar Auditivo/fisiologia , Sequência de Bases , Análise Mutacional de DNA , Eletrorretinografia , Potenciais Evocados Auditivos do Tronco Encefálico/fisiologia , Potenciais Evocados Visuais/fisiologia , Feminino , Fundo de Olho , Ligação Genética , Humanos , Masculino , Dados de Sequência Molecular , Fibras Nervosas/patologia , Atrofias Ópticas Hereditárias/fisiopatologia , Emissões Otoacústicas Espontâneas/fisiologia , Linhagem , Neurônios Retinianos/patologia , Adulto JovemRESUMO
Proliferative vasculopathy and hydranencephaly-hydrocephaly syndrome (PVHH), also known as Fowler syndrome, is an autosomal-recessively inherited prenatal lethal disorder characterized by hydranencephaly; brain stem, basal ganglia, and spinal cord diffuse clastic ischemic lesions with calcifications; glomeruloid vasculopathy of the central nervous system and retinal vessels; and a fetal akinesia deformation sequence (FADS) with muscular neurogenic atrophy. To identify the molecular basis for Fowler syndrome, we performed autozygosity mapping studies in three consanguineous families. The results of SNP microarrays and microsatellite marker genotyping demonstrated linkage to chromosome 14q24.3. Direct sequencing of candidate genes within the target interval revealed five different germline mutations in FLVCR2 in five families with Fowler syndrome. FLVCR2 encodes a transmembrane transporter of the major facilitator superfamily (MFS) hypothesized to be involved in regulation of growth, calcium exchange, and homeostasis. This is the first gene to be associated with Fowler syndrome, and this finding provides a basis for further studies to elucidate the pathogenetic mechanisms and phenotypic spectrum of associated disorders.
Assuntos
Mutação em Linhagem Germinativa , Hidranencefalia/genética , Hidrocefalia/genética , Proteínas de Membrana Transportadoras/genética , Receptores Virais/genética , Doenças Vasculares/genética , Anormalidades Múltiplas/genética , Sequência de Aminoácidos , Substituição de Aminoácidos , Animais , Sequência de Bases , Cromossomos Humanos Par 14/genética , Consanguinidade , Sequência Conservada , DNA/genética , Feminino , Genes Recessivos , Humanos , Masculino , Camundongos , Modelos Moleculares , Dados de Sequência Molecular , Análise de Sequência com Séries de Oligonucleotídeos , Linhagem , Fenótipo , Polimorfismo de Nucleotídeo Único , Gravidez , Estrutura Terciária de Proteína , Homologia de Sequência de Aminoácidos , SíndromeRESUMO
The histiocytoses are a heterogeneous group of disorders characterised by an excessive number of histiocytes. In most cases the pathophysiology is unclear and treatment is nonspecific. Faisalabad histiocytosis (FHC) (MIM 602782) has been classed as an autosomal recessively inherited form of histiocytosis with similarities to Rosai-Dorfman disease (RDD) (also known as sinus histiocytosis with massive lymphadenopathy (SHML)). To elucidate the molecular basis of FHC, we performed autozygosity mapping studies in a large consanguineous family and identified a novel locus at chromosome 10q22.1. Mutation analysis of candidate genes within the target interval identified biallelic germline mutations in SLC29A3 in the FHC kindred and in two families reported to have familial RDD. Analysis of SLC29A3 expression during mouse embryogenesis revealed widespread expression by e14.5 with prominent expression in the central nervous system, eye, inner ear, and epithelial tissues including the gastrointestinal tract. SLC29A3 encodes an intracellular equilibrative nucleoside transporter (hENT3) with affinity for adenosine. Recently germline mutations in SLC29A3 were also described in two rare autosomal recessive disorders with overlapping phenotypes: (a) H syndrome (MIM 612391) that is characterised by cutaneous hyperpigmentation and hypertrichosis, hepatomegaly, heart anomalies, hearing loss, and hypogonadism; and (b) PHID (pigmented hypertrichosis with insulin-dependent diabetes mellitus) syndrome. Our findings suggest that a variety of clinical diagnoses (H and PHID syndromes, FHC, and familial RDD) can be included in a new diagnostic category of SLC29A3 spectrum disorder.
Assuntos
Histiocitose Sinusal/genética , Mutação/genética , Proteínas de Transporte de Nucleosídeos/genética , Alelos , Animais , Sequência de Bases , Neoplasias da Mama/genética , Neoplasias da Mama/patologia , Linhagem Celular Tumoral , Proliferação de Células , Cromossomos Humanos Par 10/genética , Ensaio de Unidades Formadoras de Colônias , Análise Mutacional de DNA , Embrião de Mamíferos/metabolismo , Família , Feminino , Regulação da Expressão Gênica , Loci Gênicos/genética , Histiocitose Sinusal/patologia , Humanos , Camundongos , Dados de Sequência Molecular , Proteínas de Transporte de Nucleosídeos/metabolismo , Mapeamento Físico do Cromossomo , RNA Interferente Pequeno/metabolismo , Síndrome , Neoplasias da Bexiga Urinária/genética , Neoplasias da Bexiga Urinária/patologiaRESUMO
Hereditary folate malabsorption (HFM) is a rare autosomal recessive disorder which is characterized by impaired intestinal folate malabsorption and impaired folate transport into the central nervous system. Mutations in the intestinal folate transporter PCFT have been reported previously in only 10 individuals with this disorder. The purpose of the current study was to describe the clinical phenotype and determine the molecular basis for this disorder in a family with four affected individuals. A consanguineous family of Pakistani origin with autosomal recessive HFM was ascertained and clinically phenotyped. After genetic linkage studies all coding exons of the PCFT gene were screened for mutations by direct sequencing. The clinical phenotype of four affected patients is described. Direct sequencing of PCFT revealed a novel homozygous frameshift mutation (c.194dupG) at a mononucleotide repeat in exon 1 predicted to result in a truncated protein (p.Cys66LeufsX99). This report extends current knowledge on the phenotypic manifestations of HFM and the PCFT mutation spectrum.
Assuntos
Ácido Fólico/metabolismo , Mutação da Fase de Leitura , Síndromes de Malabsorção/genética , Proteínas de Membrana Transportadoras/genética , Adulto , Criança , Consanguinidade , Família , Feminino , Humanos , Absorção Intestinal/genética , Síndromes de Malabsorção/metabolismo , Síndromes de Malabsorção/fisiopatologia , Masculino , Paquistão , Linhagem , Fenótipo , Transportador de Folato Acoplado a PrótonRESUMO
PURPOSE: To identify the molecular basis for autosomal recessively inherited congenital non-syndromic pulverulent cataracts in a consanguineous family with four affected children. METHODS: An autozygosity mapping strategy using high density SNP microarrays and microsatellite markers was employed to detect regions of homozygosity. Subsequently good candidate genes were screened for mutations by direct sequencing. RESULTS: The SNP microarray data demonstrated a 24.96 Mb region of homozygosity at 22q11.21-22q13.2 which was confirmed by microsatellite marker analysis. The candidate target region contained the beta-crystallin gene cluster and direct sequencing in affected family members revealed a novel mutation in CRYBB1 (c.2T>A; p.Met1Lys). CONCLUSIONS: To our knowledge this is the first case of an initiation codon mutation in a human crystallin gene, and only the second report of a CRYBB1 mutation associated with autosomal recessive congenital cataracts. In addition, although a number of genetic causes of autosomal dominant pulverulent cataracts have been identified (including CRYBB1) this is the first gene to have been implicated in autosomal recessive nuclear pulverulent cataract.
Assuntos
Catarata/genética , Códon de Iniciação/genética , Genes Recessivos , Polimorfismo de Nucleotídeo Único , Cadeia B de beta-Cristalina/genética , Análise Mutacional de DNA , Família , Humanos , Repetições de Microssatélites , Análise de Sequência com Séries de OligonucleotídeosRESUMO
Genetic variants of the SLC6A3 gene that encodes the human dopamine transporter (DAT) have been linked to a variety of neuropsychiatric disorders, particularly attention deficit hyperactivity disorder. In addition, the homozygous Slc6a3 knockout mouse displays a hyperactivity phenotype. Here, we analyzed 2 unrelated consanguineous families with infantile parkinsonism-dystonia (IPD) syndrome and identified homozygous missense SLC6A3 mutations (p.L368Q and p.P395L) in both families. Functional studies demonstrated that both mutations were loss-of-function mutations that severely reduced levels of mature (85-kDa) DAT while having a differential effect on the apparent binding affinity of dopamine. Thus, in humans, loss-of-function SLC6A3 mutations that impair DAT-mediated dopamine transport activity are associated with an early-onset complex movement disorder. Identification of the molecular basis of IPD suggests SLC6A3 as a candidate susceptibility gene for other movement disorders associated with parkinsonism and/or dystonic features.
Assuntos
Proteínas da Membrana Plasmática de Transporte de Dopamina/metabolismo , Distonia/metabolismo , Homozigoto , Transtornos Parkinsonianos/metabolismo , Sequência de Aminoácidos , Animais , Sequência de Bases , Criança , Pré-Escolar , Cromossomos Humanos Par 5/genética , Proteínas da Membrana Plasmática de Transporte de Dopamina/química , Proteínas da Membrana Plasmática de Transporte de Dopamina/genética , Distonia/genética , Feminino , Humanos , Masculino , Repetições de Microssatélites/genética , Dados de Sequência Molecular , Mutação/genética , Análise de Sequência com Séries de Oligonucleotídeos , Transtornos Parkinsonianos/genética , Linhagem , Fenótipo , Alinhamento de Sequência , Homologia de Sequência de AminoácidosRESUMO
Beckwith-Wiedemann syndrome (BWS) is a fetal overgrowth and human imprinting disorder resulting from the deregulation of a number of genes, including IGF2 and CDKN1C, in the imprinted gene cluster on chromosome 11p15.5. Most cases are sporadic and result from epimutations at either of the two 11p15.5 imprinting centres (IC1 and IC2). However, rare familial cases may be associated with germline 11p15.5 deletions causing abnormal imprinting in cis. We report a family with BWS and an IC2 epimutation in which affected siblings had inherited different parental 11p15.5 alleles excluding an in cis mechanism. Using a positional-candidate gene approach, we found that the mother was homozygous for a frameshift mutation in exon 6 of NLRP2. While germline mutations in NLRP7 have previously been associated with familial hydatidiform mole, this is the first description of NLRP2 mutation in human disease and the first report of a trans mechanism for disordered imprinting in BWS. These observations are consistent with the hypothesis that NLRP2 has a previously unrecognised role in establishing or maintaining genomic imprinting in humans.
Assuntos
Proteínas Adaptadoras de Transdução de Sinal/genética , Síndrome de Beckwith-Wiedemann/genética , Impressão Genômica , Proteínas Reguladoras de Apoptose , Cromossomos Humanos Par 11 , Éxons , Saúde da Família , Feminino , Mutação da Fase de Leitura , Homozigoto , Humanos , MãesRESUMO
Bardet-Biedl syndrome (BBS) is a genetically heterogeneous autosomal recessive disorder characterized by variable obesity, pigmentary retinopathy, polydactyly, mental retardation, hypogonadism and renal failure. In order to identify novel BBS loci we undertook autozygosity mapping studies using high-density SNP microarrays in consanguineous kindreds. We mapped a BBS locus to a 10.1 Mb region at 12q15-q21.2 in a large Omani BBS family (peak lod score 8.3 at theta = 0.0 for marker D12S1722) that contained the recently described BBS10 locus. Mutation analysis of candidate genes within the target interval, including the BBS10 gene, revealed a homozygous frameshift mutation in FLJ23560 and mutations were also detected in four smaller consanguineous families with regions of autozygosity at 12q21.2. These findings (a) confirm a previous report that FLJ23560 (BBS10) mutations are a significant cause of BBS, and (b) further demonstrate the utility of high-density SNP array mapping in consanguineous families for the mapping and identification of recessive disease genes.
Assuntos
Síndrome de Bardet-Biedl/genética , Chaperoninas/genética , Cromossomos Humanos Par 12/genética , Adulto , Criança , Pré-Escolar , Consanguinidade , Análise Mutacional de DNA , Feminino , Genes Recessivos , Chaperoninas do Grupo II , Homozigoto , Humanos , Masculino , Análise de Sequência com Séries de Oligonucleotídeos , Omã , Linhagem , Mapeamento Físico do Cromossomo , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Multiple pterygium syndromes (MPSs) comprise a group of multiple-congenital-anomaly disorders characterized by webbing (pterygia) of the neck, elbows, and/or knees and joint contractures (arthrogryposis). In addition, a variety of developmental defects (e.g., vertebral anomalies) may occur. MPSs are phenotypically and genetically heterogeneous but are traditionally divided into prenatally lethal and nonlethal (Escobar) types. To elucidate the pathogenesis of MPS, we undertook a genomewide linkage scan of a large consanguineous family and mapped a locus to 2q36-37. We then identified germline-inactivating mutations in the embryonal acetylcholine receptor gamma subunit (CHRNG) in families with both lethal and nonlethal MPSs. These findings extend the role of acetylcholine receptor dysfunction in human disease and provide new insights into the pathogenesis and management of fetal akinesia syndromes.
Assuntos
Anormalidades Múltiplas/genética , Feto/anormalidades , Subunidades Proteicas/genética , Receptores Colinérgicos/genética , Anormalidades Múltiplas/embriologia , Adolescente , Cromossomos Humanos Par 2 , Feminino , Variação Genética , Humanos , Lactente , Masculino , Linhagem , SíndromeRESUMO
Neurodegenerative disorders with high brain iron include Parkinson disease, Alzheimer disease and several childhood genetic disorders categorized as neuroaxonal dystrophies. We mapped a locus for infantile neuroaxonal dystrophy (INAD) and neurodegeneration with brain iron accumulation (NBIA) to chromosome 22q12-q13 and identified mutations in PLA2G6, encoding a calcium-independent group VI phospholipase A2, in NBIA, INAD and the related Karak syndrome. This discovery implicates phospholipases in the pathogenesis of neurodegenerative disorders with iron dyshomeostasis.
Assuntos
Encéfalo/metabolismo , Transtornos Heredodegenerativos do Sistema Nervoso/genética , Transtornos Heredodegenerativos do Sistema Nervoso/metabolismo , Ferro/metabolismo , Mutação , Fosfolipases A/genética , Cromossomos Humanos Par 22/genética , Feminino , Humanos , Masculino , Distrofias Neuroaxonais/genética , Distrofias Neuroaxonais/metabolismo , Fosfolipases A/química , Fosfolipases A2 , SíndromeRESUMO
Meckel-Gruber syndrome is a severe autosomal, recessively inherited disorder characterized by bilateral renal cystic dysplasia, developmental defects of the central nervous system (most commonly occipital encephalocele), hepatic ductal dysplasia and cysts and polydactyly. MKS is genetically heterogeneous, with three loci mapped: MKS1, 17q21-24 (ref. 4); MKS2, 11q13 (ref. 5) and MKS3 (ref. 6). We have refined MKS3 mapping to a 12.67-Mb interval (8q21.13-q22.1) that is syntenic to the Wpk locus in rat, which is a model with polycystic kidney disease, agenesis of the corpus callosum and hydrocephalus. Positional cloning of the Wpk gene suggested a MKS3 candidate gene, TMEM67, for which we identified pathogenic mutations for five MKS3-linked consanguineous families. MKS3 is a previously uncharacterized, evolutionarily conserved gene that is expressed at moderate levels in fetal brain, liver and kidney but has widespread, low levels of expression. It encodes a 995-amino acid seven-transmembrane receptor protein of unknown function that we have called meckelin.
Assuntos
Anormalidades Múltiplas/genética , Mutação/genética , Proteínas/genética , Ratos Mutantes/genética , Animais , Sequência de Bases , Análise Mutacional de DNA , Modelos Animais de Doenças , Éxons/genética , Feminino , Marcadores Genéticos , Haplótipos , Humanos , Íntrons/genética , Masculino , Proteínas de Membrana , Dados de Sequência Molecular , Defeitos do Tubo Neural/genética , Linhagem , Mapeamento Físico do Cromossomo , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Ratos , Ratos Wistar , SíndromeRESUMO
Hermansky-Pudlak syndrome (HPS) is genetically heterogeneous, and mutations in seven genes have been reported to cause HPS. Autozygosity mapping studies were undertaken in a large consanguineous family with HPS. Affected individuals displayed features of incomplete oculocutaneous albinism and platelet dysfunction. Skin biopsy demonstrated abnormal aggregates of melanosomes within basal epidermal keratinocytes. A homozygous germline frameshift mutation in BLOC1S3 (p.Gln150ArgfsX75) was identified in all affected individuals. BLOC1S3 mutations have not been previously described in patients with HPS, but BLOC1S3 encodes a subunit of the biogenesis of lysosome-related organelles complex 1 (BLOC-1). Mutations in other BLOC-1 subunits have been associated with an HPS phenotype in humans and/or mouse, and a nonsense mutation in the murine orthologue of BLOC1S3 causes the reduced pigmentation (rp) model of HPS. Interestingly, eye pigment formation is reported to be normal in rp, but we found visual defects (nystagmus, iris transilluminancy, foveal hypoplasia, reduced visual acuity, and evidence of optic pathway misrouting) in affected individuals. These findings define a novel form of human HPS (HPS8) and extend genotype-phenotype correlations in HPS.
Assuntos
Proteínas de Transporte/genética , Cromossomos Humanos Par 19/genética , Mutação da Fase de Leitura/genética , Síndrome de Hermanski-Pudlak/genética , Fenótipo , Trifosfato de Adenosina/metabolismo , Adolescente , Adulto , Linhagem Celular Tumoral , Criança , Epiderme/ultraestrutura , Olho/patologia , Feminino , Síndrome de Hermanski-Pudlak/patologia , Humanos , Masculino , Microscopia Eletrônica de Transmissão , Análise de Sequência com Séries de Oligonucleotídeos , Paquistão , Linhagem , Agregação Plaquetária/genética , Polimorfismo de Nucleotídeo ÚnicoRESUMO
Isolated (non-syndromic) congenital cataract may be inherited as an autosomal dominant, autosomal recessive, or X-linked recessive trait. Considerable progress has been made in identifying genes and loci for dominantly inherited cataract, but the molecular basis for autosomal recessive disease is less well defined. Hence we undertook genetic linkage studies in four consanguineous Pakistani families with non-syndromic autosomal recessive congenital cataracts. In two families linkage to a 38 cM region 9q13-q22 was detected. Although a locus for recessive congenital cataracts had not been mapped previously to this region, the target interval encompasses the candidate region autosomal recessive adult-onset pulverulent cataracts (CAAR). The CAAR was mapped previously to 9q13-q22, and may therefore be allelic to non-syndromic autosomal recessive congenital cataracts. The other two families did not demonstrate linkage to 9q, but both had a region of homozygosity at 16q22 containing the heat shock transcription factor 4 (HSF4) gene. The HSF4 mutations have been reported in four families with autosomal dominant cataracts and, recently, in a single kindred with autosomal recessive congenital cataract. Mutation analysis of HSF4 revealed homozygous mutations (p.Arg175Pro and c.595_599delGGGCC, respectively) in the two families. These findings confirm that mutations in HSF4 may result in both autosomal dominant and autosomal recessive congenital cataract, and highlight the locus heterogeneity in autosomal recessive congenital cataract.