RESUMEN
The precise control of eye size is essential for normal vision. TMEM98 is a highly conserved and widely expressed gene which appears to be involved in eye size regulation. Mutations in human TMEM98 are found in patients with nanophthalmos (very small eyes) and variants near the gene are associated in population studies with myopia and increased eye size. As complete loss of function mutations in mouse Tmem98 result in perinatal lethality, we produced mice deficient for Tmem98 in the retinal pigment epithelium (RPE), where Tmem98 is highly expressed. These mice have greatly enlarged eyes that are very fragile with very thin retinas, compressed choroid and thin sclera. To gain insight into the mechanism of action we used a proximity labelling approach to discover interacting proteins and identified MYRF as an interacting partner. Mutations of MYRF are also associated with nanophthalmos. The protein is an endoplasmic reticulum-tethered transcription factor which undergoes autoproteolytic cleavage to liberate the N-terminal part which then translocates to the nucleus where it acts as a transcription factor. We find that TMEM98 inhibits the self-cleavage of MYRF, in a novel regulatory mechanism. In RPE lacking TMEM98, MYRF is ectopically activated and abnormally localised to the nuclei. Our findings highlight the importance of the interplay between TMEM98 and MYRF in determining the size of the eye.
Asunto(s)
Ojo/anatomía & histología , Ojo/metabolismo , Proteínas de la Membrana/metabolismo , Factores de Transcripción/antagonistas & inhibidores , Animales , Electrorretinografía , Anomalías del Ojo/genética , Femenino , Eliminación de Gen , Mutación con Pérdida de Función , Masculino , Proteínas de la Membrana/genética , Ratones , Ratones Noqueados , Tamaño de los Órganos/genética , Unión Proteica , Transporte de Proteínas , Epitelio Pigmentado de la Retina/anomalías , Epitelio Pigmentado de la Retina/metabolismo , Retinaldehído/metabolismo , Factores de Transcripción/química , Factores de Transcripción/metabolismoRESUMEN
Oculocutaneous albinism (OCA) is a heritable disorder of pigment production that manifests as hypopigmentation and altered eye development. Exon sequencing of known OCA genes is unsuccessful in producing a complete molecular diagnosis for a significant number of affected individuals. We sequenced the DNA of individuals with OCA using short-read custom capture sequencing that targeted coding, intronic, and noncoding regulatory regions of known OCA genes, and genome-wide association study-associated pigmentation loci. We identified an OCA2 complex structural variant (CxSV), defined by a 143 kb inverted segment reintroduced in intron 1, upstream of the native location. The corresponding CxSV junctions were observed in 11/390 probands screened. The 143 kb CxSV presents in one family as a copy number variant duplication for the 143 kb region. In the remaining 10/11 families, the 143 kb CxSV acquired an additional 184 kb deletion across the same region, restoring exons 3-19 of OCA2 to a copy-number neutral state. Allele-associated haplotype analysis found rare SNVs rs374519281 and rs139696407 are linked with the 143 kb CxSV in both OCA2 alleles. For individuals in which customary molecular evaluation does not reveal a biallelic OCA diagnosis, we recommend preliminary screening for these haplotype-associated rare variants, followed by junction-specific validation for the OCA2 143 kb CxSV.
Asunto(s)
Albinismo Oculocutáneo , Estudio de Asociación del Genoma Completo , Albinismo Oculocutáneo/diagnóstico , Albinismo Oculocutáneo/genética , Alelos , Humanos , Proteínas de Transporte de Membrana/genética , MutaciónRESUMEN
[This corrects the article DOI: 10.1371/journal.pgen.1002114.].
RESUMEN
During neurotransmission, synaptic vesicles undergo multiple rounds of exo-endocytosis, involving recycling and/or degradation of synaptic proteins. While ubiquitin signaling at synapses is essential for neural function, it has been assumed that synaptic proteostasis requires the ubiquitin-proteasome system (UPS). We demonstrate here that turnover of synaptic membrane proteins via the endolysosomal pathway is essential for synaptic function. In both human and mouse, hypomorphic mutations in the ubiquitin adaptor protein PLAA cause an infantile-lethal neurodysfunction syndrome with seizures. Resulting from perturbed endolysosomal degradation, Plaa mutant neurons accumulate K63-polyubiquitylated proteins and synaptic membrane proteins, disrupting synaptic vesicle recycling and neurotransmission. Through characterization of this neurological intracellular trafficking disorder, we establish the importance of ubiquitin-mediated endolysosomal trafficking at the synapse.
Asunto(s)
Epilepsia/genética , Proteínas/genética , Espasmos Infantiles/genética , Transmisión Sináptica , Proteínas Adaptadoras Transductoras de Señales/genética , Proteínas Adaptadoras Transductoras de Señales/metabolismo , Animales , Modelos Animales de Enfermedad , Epilepsia/diagnóstico , Fibroblastos/metabolismo , Técnicas de Genotipaje , Humanos , Lactante , Recién Nacido , Imagen por Resonancia Magnética , Ratones , Ratones Transgénicos , Mutación , Complejo de la Endopetidasa Proteasomal/genética , Complejo de la Endopetidasa Proteasomal/metabolismo , Conformación Proteica , Proteínas/metabolismo , Células de Purkinje/metabolismo , Espasmos Infantiles/diagnóstico , Vesículas Sinápticas/metabolismo , Transcriptoma , Ubiquitina/genética , Ubiquitina/metabolismoRESUMEN
Melanocyte development provides an excellent model for studying more complex developmental processes. Melanocytes have an apparently simple aetiology, differentiating from the neural crest and migrating through the developing embryo to specific locations within the skin and hair follicles, and to other sites in the body. The study of pigmentation mutations in the mouse provided the initial key to identifying the genes and proteins involved in melanocyte development. In addition, work on chicken has provided important embryological and molecular insights, whereas studies in zebrafish have allowed live imaging as well as genetic and transgenic approaches. This cross-species approach is powerful and, as we review here, has resulted in a detailed understanding of melanocyte development and differentiation, melanocyte stem cells and the role of the melanocyte lineage in diseases such as melanoma.
Asunto(s)
Melanocitos/citología , Melanocitos/metabolismo , Animales , Humanos , Melanoma/metabolismo , Melanoma/patología , Factor de Transcripción Asociado a Microftalmía/metabolismo , Cresta Neural/citología , Células Madre/citología , Células Madre/metabolismoRESUMEN
We report genome sequences of 17 inbred strains of laboratory mice and identify almost ten times more variants than previously known. We use these genomes to explore the phylogenetic history of the laboratory mouse and to examine the functional consequences of allele-specific variation on transcript abundance, revealing that at least 12% of transcripts show a significant tissue-specific expression bias. By identifying candidate functional variants at 718 quantitative trait loci we show that the molecular nature of functional variants and their position relative to genes vary according to the effect size of the locus. These sequences provide a starting point for a new era in the functional analysis of a key model organism.
Asunto(s)
Regulación de la Expresión Génica/genética , Variación Genética/genética , Genoma/genética , Ratones Endogámicos/genética , Ratones/genética , Fenotipo , Alelos , Animales , Animales de Laboratorio/genética , Genómica , Ratones/clasificación , Ratones Endogámicos C57BL/genética , Filogenia , Sitios de Carácter Cuantitativo/genéticaRESUMEN
Spinster homolog 2 (Spns2) acts as a Sphingosine-1-phosphate (S1P) transporter in zebrafish and mice, regulating heart development and lymphocyte trafficking respectively. S1P is a biologically active lysophospholipid with multiple roles in signalling. The mechanism of action of Spns2 is still elusive in mammals. Here, we report that Spns2-deficient mice rapidly lost auditory sensitivity and endocochlear potential (EP) from 2 to 3 weeks old. We found progressive degeneration of sensory hair cells in the organ of Corti, but the earliest defect was a decline in the EP, suggesting that dysfunction of the lateral wall was the primary lesion. In the lateral wall of adult mutants, we observed structural changes of marginal cell boundaries and of strial capillaries, and reduced expression of several key proteins involved in the generation of the EP (Kcnj10, Kcnq1, Gjb2 and Gjb6), but these changes were likely to be secondary. Permeability of the boundaries of the stria vascularis and of the strial capillaries appeared normal. We also found focal retinal degeneration and anomalies of retinal capillaries together with anterior eye defects in Spns2 mutant mice. Targeted inactivation of Spns2 in red blood cells, platelets, or lymphatic or vascular endothelial cells did not affect hearing, but targeted ablation of Spns2 in the cochlea using a Sox10-Cre allele produced a similar auditory phenotype to the original mutation, suggesting that local Spns2 expression is critical for hearing in mammals. These findings indicate that Spns2 is required for normal maintenance of the EP and hence for normal auditory function, and support a role for S1P signalling in hearing.
Asunto(s)
Proteínas de Transporte de Anión/genética , Cóclea/patología , Oído Interno/patología , Pérdida Auditiva/genética , Edad de Inicio , Animales , Proteínas de Transporte de Anión/deficiencia , Proteínas de Transporte de Anión/metabolismo , Segmento Anterior del Ojo/metabolismo , Segmento Anterior del Ojo/patología , Cóclea/metabolismo , Conexina 26 , Conexinas , Células Ciliadas Auditivas/metabolismo , Células Ciliadas Auditivas/patología , Pérdida Auditiva/metabolismo , Pérdida Auditiva/patología , Lisofosfolípidos/metabolismo , Ratones , Organogénesis/genética , Esfingosina/análogos & derivados , Esfingosina/metabolismo , Estría Vascular/patología , Pez CebraRESUMEN
Mutations in the LIM-homeodomain transcription factor LMX1B cause nail-patella syndrome, an autosomal dominant pleiotrophic human disorder in which nail, patella and elbow dysplasia is associated with other skeletal abnormalities and variably nephropathy and glaucoma. It is thought to be a haploinsufficient disorder. Studies in the mouse have shown that during development Lmx1b controls limb dorsal-ventral patterning and is also required for kidney and eye development, midbrain-hindbrain boundary establishment and the specification of specific neuronal subtypes. Mice completely deficient for Lmx1b die at birth. In contrast to the situation in humans, heterozygous null mice do not have a mutant phenotype. Here we report a novel mouse mutant Icst, an N-ethyl-N-nitrosourea-induced missense substitution, V265D, in the homeodomain of LMX1B that abolishes DNA binding and thereby the ability to transactivate other genes. Although the homozygous phenotypic consequences of Icst and the null allele of Lmx1b are the same, heterozygous Icst elicits a phenotype whilst the null allele does not. Heterozygous Icst causes glaucomatous eye defects and is semi-lethal, probably due to kidney failure. We show that the null phenotype is rescued more effectively by an Lmx1b transgene than is Icst. Co-immunoprecipitation experiments show that both wild-type and Icst LMX1B are found in complexes with LIM domain binding protein 1 (LDB1), resulting in lower levels of functional LMX1B in Icst heterozygotes than null heterozygotes. We conclude that Icst is a dominant-negative allele of Lmx1b. These findings indicate a reassessment of whether nail-patella syndrome is always haploinsufficient. Furthermore, Icst is a rare example of a model of human glaucoma caused by mutation of the same gene in humans and mice.
Asunto(s)
Genes Dominantes , Genes Letales , Glaucoma/genética , Proteínas con Homeodominio LIM/genética , Factores de Transcripción/genética , Alelos , Animales , Tipificación del Cuerpo , Dimerización , Heterocigoto , Ratones , Ratones Transgénicos , Mutación MissenseRESUMEN
Cilia are highly conserved microtubule-based structures that perform a variety of sensory and motility functions during development and adult homeostasis. In humans, defects specifically affecting motile cilia lead to chronic airway infections, infertility and laterality defects in the genetically heterogeneous disorder Primary Ciliary Dyskinesia (PCD). Using the comparatively simple Drosophila system, in which mechanosensory neurons possess modified motile cilia, we employed a recently elucidated cilia transcriptional RFX-FOX code to identify novel PCD candidate genes. Here, we report characterization of CG31320/HEATR2, which plays a conserved critical role in forming the axonemal dynein arms required for ciliary motility in both flies and humans. Inner and outer arm dyneins are absent from axonemes of CG31320 mutant flies and from PCD individuals with a novel splice-acceptor HEATR2 mutation. Functional conservation of closely arranged RFX-FOX binding sites upstream of HEATR2 orthologues may drive higher cytoplasmic expression of HEATR2 during early motile ciliogenesis. Immunoprecipitation reveals HEATR2 interacts with DNAI2, but not HSP70 or HSP90, distinguishing it from the client/chaperone functions described for other cytoplasmic proteins required for dynein arm assembly such as DNAAF1-4. These data implicate CG31320/HEATR2 in a growing intracellular pre-assembly and transport network that is necessary to deliver functional dynein machinery to the ciliary compartment for integration into the motile axoneme.
Asunto(s)
Cilios/metabolismo , Cilios/fisiología , Proteínas/metabolismo , Animales , Dineínas Axonemales , Axonema/genética , Axonema/metabolismo , Sitios de Unión/genética , Línea Celular , Preescolar , Cilios/genética , Trastornos de la Motilidad Ciliar/genética , Trastornos de la Motilidad Ciliar/metabolismo , Drosophila/genética , Drosophila/metabolismo , Dineínas/genética , Dineínas/metabolismo , Femenino , Humanos , Síndrome de Kartagener/genética , Síndrome de Kartagener/metabolismo , Masculino , Mutación/genética , Linaje , Fenotipo , Proteínas/genética , Transcripción Genética/genéticaRESUMEN
Defects in cilium and centrosome function result in a spectrum of clinically-related disorders, known as ciliopathies. However, the complex molecular composition of these structures confounds functional dissection of what any individual gene product is doing under normal and disease conditions. As part of an siRNA screen for genes involved in mammalian ciliogenesis, we and others have identified the conserved centrosomal protein Azi1/Cep131 as required for cilia formation, supporting previous Danio rerio and Drosophila melanogaster mutant studies. Acute loss of Azi1 by knock-down in mouse fibroblasts leads to a robust reduction in ciliogenesis, which we rescue by expressing siRNA-resistant Azi1-GFP. Localisation studies show Azi1 localises to centriolar satellites, and traffics along microtubules becoming enriched around the basal body. Azi1 also localises to the transition zone, a structure important for regulating traffic into the ciliary compartment. To study the requirement of Azi1 during development and tissue homeostasis, Azi1 null mice were generated (Azi1(Gt/Gt)). Surprisingly, Azi1(Gt/Gt) MEFs have no discernible ciliary phenotype and moreover are resistant to Azi1 siRNA knock-down, demonstrating that a compensation mechanism exists to allow ciliogenesis to proceed despite the lack of Azi1. Cilia throughout Azi1 null mice are functionally normal, as embryonic patterning and adult homeostasis are grossly unaffected. However, in the highly specialised sperm flagella, the loss of Azi1 is not compensated, leading to striking microtubule-based trafficking defects in both the manchette and the flagella, resulting in male infertility. Our analysis of Azi1 knock-down (acute loss) versus gene deletion (chronic loss) suggests that Azi1 plays a conserved, but non-essential trafficking role in ciliogenesis. Importantly, our in vivo analysis reveals Azi1 mediates novel trafficking functions necessary for flagellogenesis. Our study highlights the importance of both acute removal of a protein, in addition to mouse knock-out studies, when functionally characterising candidates for human disease.
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Cilios/genética , Infertilidad Masculina/genética , Proteínas/genética , Cola del Espermatozoide/patología , Animales , Proteínas de Ciclo Celular , Centriolos/genética , Centriolos/metabolismo , Cilios/patología , Proteínas del Citoesqueleto , Flagelos/metabolismo , Flagelos/patología , Regulación del Desarrollo de la Expresión Génica , Humanos , Infertilidad Masculina/etiología , Masculino , Ratones , Ratones Noqueados , Microtúbulos/metabolismo , Microtúbulos/patología , Proteínas/metabolismo , ARN Interferente PequeñoRESUMEN
Following domestication, livestock breeds have experienced intense selection pressures for the development of desirable traits. This has resulted in a large diversity of breeds that display variation in many phenotypic traits, such as coat colour, muscle composition, early maturity, growth rate, body size, reproduction, and behaviour. To better understand the relationship between genomic composition and phenotypic diversity arising from breed development, the genomes of 13 traditional and commercial European pig breeds were scanned for signatures of diversifying selection using the Porcine60K SNP chip, applying a between-population (differentiation) approach. Signatures of diversifying selection between breeds were found in genomic regions associated with traits related to breed standard criteria, such as coat colour and ear morphology. Amino acid differences in the EDNRB gene appear to be associated with one of these signatures, and variation in the KITLG gene may be associated with another. Other selection signals were found in genomic regions including QTLs and genes associated with production traits such as reproduction, growth, and fat deposition. Some selection signatures were associated with regions showing evidence of introgression from Asian breeds. When the European breeds were compared with wild boar, genomic regions with high levels of differentiation harboured genes related to bone formation, growth, and fat deposition.
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Cruzamiento , Sus scrofa , Animales , Genoma , Genómica , Fenotipo , Polimorfismo de Nucleótido Simple , Sitios de Carácter Cuantitativo , Selección Genética , Sus scrofa/genética , PorcinosRESUMEN
Mp is an irradiation-induced mouse mutation associated with microphthalmia, micropinna and hind limb syndactyly. We show that Mp is caused by a 660 kb balanced inversion on chromosome 18 producing reciprocal 3-prime gene fusion events involving Fbn2 and Isoc1. The Isoc1-Fbn2 fusion gene (Isoc1(Mp)) mRNA has a frameshift and early stop codon resulting in nonsense mediated decay. Homozygous deletions of Isoc1 do not support a significant developmental role for this gene. The Fbn2-Isoc1 fusion gene (Fbn2 (Mp)) predicted protein consists of the N-terminal Fibrillin-2 (amino acids 1-2646, exons 1-62) lacking the C-terminal furin-cleavage site with a short out-of-frame extension encoded by the final exon of Isoc1. The Mp limb phenotype is consistent with that reported in Fbn2 null embryos. However, severe eye malformations, a defining feature of Mp, are not seen in Fbn2 null animals. Fibrillin-2(Mp) forms large fibrillar structures within the rough endoplasmic reticulum (rER) associated with an unfolded protein response and quantitative mass spectrometry shows a generalised defect in protein secretion in conditioned media from mutant cells. In the embryonic eye Fbn2 is expressed within the peripheral ciliary margin (CM). Mp embryos show reduced canonical Wnt-signalling in the CM - known to be essential for ciliary body development - and show subsequent aplasia of CM-derived structures. We propose that the Mp "worse-than-null" eye phenotype plausibly results from a failure in normal trafficking of proteins that are co-expressed with Fbn2 within the CM. The prediction of similar trans-acting protein effects will be an important challenge in the medical interpretation of human mutations from whole exome sequencing.
Asunto(s)
Anomalías del Ojo/genética , Proteínas de Microfilamentos/genética , Microftalmía/genética , Mutación/efectos de la radiación , Animales , Inversión Cromosómica/genética , Cromosomas Humanos Par 18/genética , Exones , Ojo/crecimiento & desarrollo , Ojo/fisiopatología , Anomalías del Ojo/fisiopatología , Fibrilina-2 , Fibrilinas , Mutación del Sistema de Lectura , Humanos , Ratones , Microftalmía/fisiopatología , Fenotipo , Sindactilia/genética , Sindactilia/fisiopatología , Vía de Señalización Wnt/genéticaRESUMEN
Defects in cilia formation and function result in a range of human skeletal and visceral abnormalities. Mutations in several genes have been identified to cause a proportion of these disorders, some of which display genetic (locus) heterogeneity. Mouse models are valuable for dissecting the function of these genes, as well as for more detailed analysis of the underlying developmental defects. The short-rib polydactyly (SRP) group of disorders are among the most severe human phenotypes caused by cilia dysfunction. We mapped the disease locus from two siblings affected by a severe form of SRP to 2p24, where we identified an in-frame homozygous deletion of exon 5 in WDR35. We subsequently found compound heterozygous missense and nonsense mutations in WDR35 in an independent second case with a similar, severe SRP phenotype. In a mouse mutation screen for developmental phenotypes, we identified a mutation in Wdr35 as the cause of midgestation lethality, with abnormalities characteristic of defects in the Hedgehog signaling pathway. We show that endogenous WDR35 localizes to cilia and centrosomes throughout the developing embryo and that human and mouse fibroblasts lacking the protein fail to produce cilia. Through structural modeling, we show that WDR35 has strong homology to the COPI coatamers involved in vesicular trafficking and that human SRP mutations affect key structural elements in WDR35. Our report expands, and sheds new light on, the pathogenesis of the SRP spectrum of ciliopathies.
Asunto(s)
Mutación , Proteínas/genética , Síndrome de Costilla Pequeña y Polidactilia/genética , Secuencia de Aminoácidos , Animales , Mapeo Cromosómico , Cilios/genética , Cilios/fisiología , Proteína Coat de Complejo I/química , Proteína Coat de Complejo I/genética , Codón sin Sentido , Proteínas del Citoesqueleto , Desarrollo Embrionario/genética , Femenino , Proteínas Hedgehog , Heterocigoto , Homocigoto , Humanos , Péptidos y Proteínas de Señalización Intracelular , Masculino , Ratones , Ratones Mutantes , Modelos Moleculares , Datos de Secuencia Molecular , Proteínas Mutantes/química , Proteínas Mutantes/genética , Mutación Missense , Fenotipo , Embarazo , Proteínas/química , Eliminación de Secuencia , Homología de Secuencia de Aminoácido , Síndrome de Costilla Pequeña y Polidactilia/embriología , Síndrome de Costilla Pequeña y Polidactilia/fisiopatologíaRESUMEN
Coordination of cell proliferation and differentiation is crucial for tissue formation, repair and regeneration. Some tissues, such as skin and blood, depend on differentiation of a pluripotent stem cell population, whereas others depend on the division of differentiated cells. In development and in the hair follicle, pigmented melanocytes are derived from undifferentiated precursor cells or stem cells. However, differentiated melanocytes may also have proliferative capacity in animals, and the potential for differentiated melanocyte cell division in development and regeneration remains largely unexplored. Here, we use time-lapse imaging of the developing zebrafish to show that while most melanocytes arise from undifferentiated precursor cells, an unexpected subpopulation of differentiated melanocytes arises by cell division. Depletion of the overall melanocyte population triggers a regeneration phase in which differentiated melanocyte division is significantly enhanced, particularly in young differentiated melanocytes. Additionally, we find reduced levels of Mitf activity using an mitfa temperature-sensitive line results in a dramatic increase in differentiated melanocyte cell division. This supports models that in addition to promoting differentiation, Mitf also promotes withdrawal from the cell cycle. We suggest differentiated cell division is relevant to melanoma progression because the human melanoma mutation MITF(4T)(Δ)(2B) promotes increased and serial differentiated melanocyte division in zebrafish. These results reveal a novel pathway of differentiated melanocyte division in vivo, and that Mitf activity is essential for maintaining cell cycle arrest in differentiated melanocytes.
Asunto(s)
División Celular , Melanocitos/citología , Melanocitos/metabolismo , Factor de Transcripción Asociado a Microftalmía/metabolismo , Mutación , Proteínas de Pez Cebra/metabolismo , Pez Cebra/metabolismo , Animales , Diferenciación Celular , Regulación del Desarrollo de la Expresión Génica , Humanos , Factor de Transcripción Asociado a Microftalmía/genética , Pez Cebra/embriología , Pez Cebra/genética , Proteínas de Pez Cebra/genéticaRESUMEN
Ophthalmo-acromelic syndrome (OAS), also known as Waardenburg Anophthalmia syndrome, is defined by the combination of eye malformations, most commonly bilateral anophthalmia, with post-axial oligosyndactyly. Homozygosity mapping and subsequent targeted mutation analysis of a locus on 14q24.2 identified homozygous mutations in SMOC1 (SPARC-related modular calcium binding 1) in eight unrelated families. Four of these mutations are nonsense, two frame-shift, and two missense. The missense mutations are both in the second Thyroglobulin Type-1 (Tg1) domain of the protein. The orthologous gene in the mouse, Smoc1, shows site- and stage-specific expression during eye, limb, craniofacial, and somite development. We also report a targeted pre-conditional gene-trap mutation of Smoc1 (Smoc1(tm1a)) that reduces mRNA to â¼10% of wild-type levels. This gene-trap results in highly penetrant hindlimb post-axial oligosyndactyly in homozygous mutant animals (Smoc1(tm1a/tm1a)). Eye malformations, most commonly coloboma, and cleft palate occur in a significant proportion of Smoc1(tm1a/tm1a) embryos and pups. Thus partial loss of Smoc-1 results in a convincing phenocopy of the human disease. SMOC-1 is one of the two mammalian paralogs of Drosophila Pentagone, an inhibitor of decapentaplegic. The orthologous gene in Xenopus laevis, Smoc-1, also functions as a Bone Morphogenic Protein (BMP) antagonist in early embryogenesis. Loss of BMP antagonism during mammalian development provides a plausible explanation for both the limb and eye phenotype in humans and mice.
Asunto(s)
Anoftalmos/genética , Proteína Morfogenética Ósea 1/antagonistas & inhibidores , Mutación , Osteonectina , Síndrome de Waardenburg/genética , Animales , Proteína Morfogenética Ósea 1/genética , Coloboma/genética , Análisis Mutacional de ADN , Extremidades/crecimiento & desarrollo , Ojo/crecimiento & desarrollo , Humanos , Ratones , Ratones Endogámicos C57BL , Ratones Noqueados , Modelos Animales , Osteonectina/genética , Osteonectina/metabolismo , Linaje , Sindactilia/genética , Xenopus laevisRESUMEN
Warburg Micro syndrome and Martsolf syndrome (MS) are heterogeneous autosomal-recessive developmental disorders characterized by brain, eye, and endocrine abnormalities. Causative biallelic germline mutations have been identified in RAB3GAP1, RAB3GAP2, or RAB18, each of which encode proteins involved in membrane trafficking. This report provides an up to date overview of all known disease variants identified in 29 previously published families and 52 new families. One-hundred and forty-four Micro and nine Martsolf families were investigated, identifying mutations in RAB3GAP1 in 41% of cases, mutations in RAB3GAP2 in 7% of cases, and mutations in RAB18 in 5% of cases. These are listed in Leiden Open source Variation Databases, which was created by us for all three genes. Genotype-phenotype correlations for these genes have now established that the clinical phenotypes in Micro syndrome and MS represent a phenotypic continuum related to the nature and severity of the mutations present in the disease genes, with more deleterious mutations causing Micro syndrome and milder mutations causing MS. RAB18 has not yet been linked to the RAB3 pathways, but mutations in all three genes cause an indistinguishable phenotype, making it likely that there is some overlap. There is considerable genetic heterogeneity for these disorders and further gene identification will help delineate these pathways.
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Catarata/genética , Genotipo , Hipogonadismo/genética , Discapacidad Intelectual/genética , Mutación Missense , Fenotipo , Proteínas de Unión al GTP rab/genética , Proteínas de Unión al GTP rab3/genética , Secuencia de Aminoácidos , Animales , Catarata/patología , Niño , Preescolar , Humanos , Hipogonadismo/patología , Lactante , Discapacidad Intelectual/patología , Imagen por Resonancia Magnética , Masculino , Datos de Secuencia Molecular , Homología de Secuencia de Aminoácido , Proteínas de Unión al GTP rab/química , Proteínas de Unión al GTP rab3/químicaRESUMEN
Renal-coloboma syndrome, also known as papillorenal syndrome, is an autosomal dominant human disorder in which optic disc coloboma is associated with kidney abnormalities. Mutations in the paired domain transcription factor PAX2 have been found to be the underlying cause of this disease. Disease severity varies between patients, and in some cases, renal hypoplasia has been found in the absence of any retinal defects. Here we report an N-ethyl-N-nitrosourea-induced mouse mutation, Opdc, which is an isoleucinetothreonine missense mutation, I40T, in the first α-helix of the Pax2 paired domain. The mutant protein binds target DNA sequences less strongly than the wild-type protein and acts poorly to transactivate target promoters in culture. The phenotypic consequence of this mutation on the development of the eye and ear is similar to that reported for null alleles of Pax2. However, in homozygotes, cerebellar development is normal on a genetic background in which loss of Pax2 results in failure of cerebellar formation. Moreover, there is a genetic background effect on the heterozygous phenotype such that on some strain backgrounds, kidney development is unaffected. Opdc is the first hypomorphic mutation reported for Pax2 that differs in phenotype from loss-of-function mutations. These results suggest that PAX2 is a strong candidate gene for cases in which human patients have optic disc coloboma not associated with renal dysplasia.
Asunto(s)
Coloboma/genética , Coloboma/patología , Mutación Missense , Factor de Transcripción PAX2/genética , Factor de Transcripción PAX2/metabolismo , Fenotipo , Insuficiencia Renal/genética , Insuficiencia Renal/patología , Reflujo Vesicoureteral/genética , Reflujo Vesicoureteral/patología , Anomalías Múltiples/genética , Anomalías Múltiples/patología , Animales , Proteínas de Unión al ADN/metabolismo , Regulación del Desarrollo de la Expresión Génica/genética , Genotipo , Humanos , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C3H , Ratones Endogámicos C57BL , Modelos Animales , Mutación Puntual , Activación Transcripcional/genéticaRESUMEN
Several mutant strains of mice have dark skin pigmentation due to an aberrant accumulation of pigment-producing melanocytes in the dermal layer of the skin. A new study shows that three such strains carry activating mutations in the genes encoding the G-protein subunits Galphaq or Galpha11, resulting in more pigment cell precursors and an excess of dermally retained pigment cells at birth.