常染色体隐性遗传视网膜色素变性的相关基因研究进展

视网膜色素变性 (retinitis pigmentosa,RP)是一组进行性的可致盲的单基因遗传性视网膜疾病 ,以视网膜光感受器和色素上皮功能进行性受损为主要特征。常染色体隐性视网膜色素变性 (autosom al recessive RP,ad RP)属视网膜色素变性的一种类型 ,具有遗传异质性和临床异质性。目前已克隆了 15个致病基因 ,包括 PDEA、PDEB、CNGA 1、ABCA4、RL BP1、RPE6 5、TU L P1和 CRB1等 ,现简介如下。     

常染色体隐性遗传视网膜色素变性的相关基因研究进展

视网膜色素变性（retinitis pigmentosa,RP)是一组进行性的可致盲的单基因遗传性视网膜疾病，以视网膜光感受器和色素上皮功能进行性受损为主要特征。常染色体隐性视网膜色素变性（autosoma recessive RP,adRP)属视网膜色素变性的一种类型，具有遗传异质性和临床异质性。目前巳克隆了15个致病基因，包括PDEA、PDEB、CNGA1、ABCA4、RLBP1、RPE65、TULP1和CRB1等。现简介绍下。     

X性连锁视网膜色素变性遗传学研究进展

视网膜色素变性 (retinitis pigmentosa,RP)是一组具有遗传异质性的单基因遗传性视网膜疾病。分为常染色体显性、常染色体隐性和 X-性连锁三种遗传形式。本文就 X-性连锁视网膜色素变性 (XL RP)的遗传学研究进展予以综述。     

X性连锁视同多膜色素变性遗传学研究进展

视网膜色素变性（retinitis pigmentosa,RP)是一组具有遗传异质性的单基因遗传性视网膜疾病。分为常染色体显性、常染色体隐性和X－性连锁三种遗传形式。本就X－性连锁视网膜色素变性（XLRP）的遗传学研究进展予以综述。     

1P远端RP13基因座与常染色体显性着色性视网膜炎相连锁的一个新家族

【英」／TarotelinEE…／／JMedGenet．－1996，33．518。520着色性视网膜炎（RP）是一组遗传性视iqJ膜营养不良疾病，其特征为光感受体萎缩和视网膜外周色素沉着。病人视野变狭和夜盲，在生命晚期常常以进行性减退，直至视力完全失明。RP是以X一连锁、常染色体显性和常染色体隐性遗传，同时在另一些具有表型缺陷综合征中也发现此病。这种疾病的严重性和发病年龄具有临床异质性，同时也存在大量的遗传异质B。约25％的常染色体显性着色性视网膜炎（ADRP）是由机紫质基因和另一个视网膜基因、RDS／外用蛋白穷变引起，约5％ADRP家族…     

脑源性神经营养因子在异常免疫应答相关神经系统变性疾病中的作用

神经系统变性疾病是一类由成熟神经元进行性变性、坏死所引起认知及行为异常的疾病,严重时会导致患者死亡,目前尚无有效的治疗手段。有研究表明,免疫应答异常普遍存在于中枢神经系统变性疾病过程中,并会导致蛋白质脑源性神经营养因子(BDNF)的减少,引起运动、认知及记忆等障碍。BDNF在神经系统变性疾病中免疫应答异常的作用可能涉及多种机制,虽然目前尚无定论,但BDNF相关的治疗手段,有可能从调节机体免疫能力的角度,为神经系统变性疾病的治疗提供新思路,有着重大的意义。因此,有关BDNF介导的免疫反应在神经系统变性疾病中作用的研究已成为近年来的热点。本文就此进行探讨,并对与BDNF相关的神经系统变性疾病的治疗手段进行综述。     

常染色体显性遗传视网膜色素变性的研究概况

视网膜色素变性是视网膜感光细胞和色素上皮细胞变性导致夜盲和进行性视野缺损的一类眼底遗传病。常染色体显性遗传视网膜色素变性占视网膜色素变性的20％～25％，已克隆至少11个常染色体显性遗传基因。本文就常染色体显性遗传视网膜色素变性临床分型、基因定位、克隆和治疗等方面研究进展作一综述。     

常染色体显性遗传视网膜色素变性的研究概况

视网膜色素变性是视网膜感光细胞和色素上皮细胞变性导致夜盲和进行性视野缺损的一类眼底遗传病。常染色体显性遗传视网膜色素变性占视网膜色素变性的 2 0 %～ 2 5 %,已克隆至少 11个常染色体显性遗传基因。本文就常染色体显性遗传视网膜色素变性临床分型、基因定位、克隆和治疗等方面研究进展作一综述     

免疫应答异常与中枢神经系统退变性疾病

免疫功能异常参与了中枢神经系统退变性疾病的发生。中枢免疫功能异常主要为小胶质细胞异常激活。激活的小胶质细胞可形成活性中间代谢产物、一氧化氮、促炎因子等细胞毒性物质。发病率最高的两种中枢神经系统退变性疾病阿尔茨海默病（Alzheimer′s disease,AD)和帕鑫森病（Parkinson′s disease,PD)的发生都与免疫功能异常密切相关。由于免疫功能异常特别是小胶质细胞激活普遍存在于中枢神经系统退变性疾病过程中，调节小胶质细胞功能的药物可能会具有神经保护作用，延迟甚至阻止神经元变性。     

Wnt信号通路调控神经干细胞向多巴胺神经元分化的研究进展

<正>帕金森病(Parkinson's disease,PD)是一种常见的严重中枢退行性疾病萁主要病理特征是中脑黑质多巴胺(Dopamine,DA)能神经元变性与丢失,导致纹状体内DA含量明显下降雉体外系功能失调。PD患者出现静止性震颤、动作迟缓、肌肉僵直、异常步态等症状,并呈进行性加重。临床传统药物如Levodopa(L-DOPA)等治疗能够有效改善症状,但长期用药后会出现药效的显著下降,并且诱发异常运动等严     

Molecular study of the rhodopsin gene in retinitis pigmentosa patients in the Basque Country.

Retinitis pigmentosa (RP) is a degenerative disorder affecting the outer segment of the retina and leading to night blindness and progressive visual field loss. The rhodopsin gene encodes a photolabile pigment located in the rod outer segments constituting around 80-90% of its protein content and is the initiation point for the visual cascade upon absorption of a single photon. Seventy-five unrelated, isolated RP families in the Basque Country, with at least one affected member, were diagnosed at our hospital after ophthalmic examination and electroretinogram analysis. The patients received genetic counselling according to their individual case based on their clinical diagnosis. The modes of inheritance found from pedigree studies were the following: 20% (15/75) were classified as autosomal dominant retinitis pigmentosa (ADRP), 17.33% (13/75) were autosomal recessive (ARRP), 2.66% (2/75) were unclassified (NC), and 60% (45/75) were sporadic cases (SCRP). From these families, 75 unrelated and affected index cases together with 22 affected relatives and 42 unaffected relatives were screened for mutations in the rhodopsin gene by GC clamped denaturing gradient gel electrophoresis. Our results showed that five ADRP, three ARRP, 15 SCRP, and one NC families had alterations in this gene. Only three of these alterations, that is 4% (3/75) (95% CL 0-8), appeared to be responsible for the disease. This represents a lower percentage than the 10% previously reported.     

Mapping a new genetic locus for X linked retinitis pigmentosa to Xq28

We have defined a new genetic locus for an X linked form of retinitis pigmentosa (RP) on chromosome Xq28. We examined 15 members of a family in which RP appeared to be transmitted in an X linked manner. Ocular examinations were performed, and fundus photographs and electroretinograms were obtained for selected patients. Blood samples were obtained from all patients and an additional seven family members who were not given examinations. Visual acuity in four affected individuals ranged from 20/40 to 20/80+. Patients described the onset of night blindness and colour vision defects in the second decade of life, with the earliest at 13 years of age. Examined affected individuals had constricted visual fields and retinal findings compatible with RP. Based on full field electroretinography, cone function was more severely reduced than rod function. Female carriers had no ocular signs or symptoms and slightly reduced cone electroretinographic responses. Affected and non‐affected family members were genotyped for 20 polymorphic markers on the X‐chromosome spaced at 10 cM intervals. Genotyping data were analysed using GeneMapper software. Genotyping and linkage analyses identified significant linkage to markers DXS8061, DXS1073, and DXS1108 with two point LOD scores of 2.06, 2.17, and 2.20, respectively. Haplotype analysis revealed segregation of the disease phenotype with markers at Xq28.     

Genetic Analysis of FAM46A in Spanish Families with Autosomal Recessive Retinitis Pigmentosa: Characterisation of Novel VNTRs

Retinitis pigmentosa (RP) is a group of retinal dystrophies characterised primarily by rod photoreceptor cell degeneration. Exhibiting great clinical and genetic heterogeneity, RP be inherited as an autosomal dominant (ad) and recessive (ar), X-linked (xl) and digenic disorder. RP25 , a locus for arRP, was mapped to chromosome 6p12.1-q14.1 where several retinal dystrophy loci are located. A gene expressed in the retina, FAM46A , mapped within the RP25 locus, and computational data revealed its involvement in retinal signalling pathways. Therefore, we chose to perform molecular evaluation of this gene as a good candidate in arRP families linked to the RP25 interval. A comprehensive bioinformatic and retinal tissue expression characterisation of FAM46A was performed, together with mutation screening of seven RP25 families.
Herein we present 4 novel sequence variants, of which one is a novel deletion within a low complexity region close to the initiation codon of FAM46A . Furthermore, we have characterised for the first time a coding tandem variation in the Caucasian population.
This study reports on bioinformatic and moleculardata for the FAM46A gene that may give a wider insight into the putative function of this gene and its pathologic relevance to RP25 and other retinal diseases mapping within the 6q chromosomal interval.     

Localization in the human retina of the X-linked retinitis pigmentosa protein RP2, its homologue cofactor C and the RP2 interacting protein Arl3

Mutations in the retinitis pigmentosa 2 (RP2) gene cause a severe form of X-linked retinal degeneration. RP2 is a ubiquitous 350 amino acid plasma membrane-associated protein, which shares homology with the tubulin-specific chaperone cofactor C. RP2 protein, like cofactor C, stimulates the GTPase activity of tubulin in combination with cofactor D. RP2 has also been shown to interact with ADP ribosylation factor-like 3 (Arl3) in a nucleotide and myristoylation-dependant manner. In this study we have examined the relationship between RP2, cofactor C and Arl3 in patient-derived cell lines and in the retina. Examination of lymphoblastoid cells from patients with an Arg120stop nonsense mutation in RP2 revealed that the expression levels of cofactor C and Arl3 were not affected by the absence of RP2. In human retina, RP2 was localized to the plasma membrane of cells throughout the retina. RP2 was present at the plasma membrane in both rod and cone photoreceptors, extending from the outer segment through the inner segment to the synaptic terminals. There was no enrichment of RP2 staining in any photoreceptor organelle. In contrast, cofactor C and Arl3 localized predominantly to the photoreceptor connecting cilium in rod and cone photoreceptors. Cofactor C was cytoplasmic in distribution, whereas Arl3 localized to other microtubule structures within all cells. Arl3 behaved as a microtubule-associated protein: it co-localized with microtubules in HeLa cells and this was enhanced following microtubule stabilization with taxol. Furthermore, Arl3 co-purified with microtubules from bovine brain. Following microtubule depolymerization with nocodazole, Arl3 relocalized to the nuclear membrane. These data suggest that RP2 functions in concert with Arl3 to link the cell membrane with the cytoskeleton in photoreceptors as part of the cell signaling or vesicular transport machinery.     

Next-generation genetic testing for retinitis pigmentosa

Molecular diagnostics for patients with retinitis pigmentosa (RP) has been hampered by extreme genetic and clinical heterogeneity, with 52 causative genes known to date. Here, we developed a comprehensive next-generation sequencing (NGS) approach for the clinical molecular diagnostics of RP. All known inherited retinal disease genes (n = 111) were captured and simultaneously analyzed using NGS in 100 RP patients without a molecular diagnosis. A systematic data analysis pipeline was developed and validated to prioritize and predict the pathogenicity of all genetic variants identified in each patient, which enabled us to reduce the number of potential pathogenic variants from approximately 1,200 to zero to nine per patient. Subsequent segregation analysis and in silico predictions of pathogenicity resulted in a molecular diagnosis in 36 RP patients, comprising 27 recessive, six dominant, and three X-linked cases. Intriguingly, De novo mutations were present in at least three out of 28 isolated cases with causative mutations. This study demonstrates the enormous potential and clinical utility of NGS in molecular diagnosis of genetically heterogeneous diseases such as RP. De novo dominant mutations appear to play a significant role in patients with isolated RP, having major implications for genetic counselling.     

Combining gene mapping and phenotype assessment for fast mutation finding in non-consanguineous autosomal recessive retinitis pigmentosa families

Among inherited retinal dystrophies, autosomal recessive retinitis pigmentosa (arRP) is the most genetically heterogenous condition with 32 genes currently known that account for ~60 % of patients. Molecular diagnosis thus requires the tedious systematic sequencing of 506 exons. To rapidly identify the causative mutations, we devised a strategy that combines gene mapping and phenotype assessment in small non-consanguineous families. Two unrelated sibships with arRP had whole-genome scan using SNP microchips. Chromosomal regions were selected by calculating a score based on SNP coverage and genotype identity of affected patients. Candidate genes from the regions with the highest scores were then selected based on phenotype concordance of affected patients with previously described phenotype for each candidate gene. For families RP127 and RP1459, 33 and 40 chromosomal regions showed possible linkage, respectively. By comparing the scores with the phenotypes, we ended with one best candidate gene for each family, namely tubby-like protein 1 (TULP1) and C2ORF71 for RP127 and RP1459, respectively. We found that RP127 patients were compound heterozygous for two novel TULP1 mutations, p.Arg311Gln and p.Arg342Gln, and that RP1459 patients were compound heterozygous for two novel C2ORF71 mutations, p.Leu777PhefsX34 and p.Leu777AsnfsX28. Phenotype assessment showed that TULP1 patients had severe early onset arRP and that C2ORF71 patients had a cone rod dystrophy type of arRP. Only two affected individuals in each sibship were sufficient to lead to mutation identification by screening the best candidate gene selected by a combination of gene mapping and phenotype characterization.     

Arg120stop nonsense mutation in the RP2 gene: mutational hotspot and germ line mosaicism?

Mutations in the RP2 gene account for up to 20% of X-linked recessive retinitis pigmentosa (RP). Arg120stop is to date the most frequently reported mutation found in RP2. Mutation screening was performed during the course of a large screening program of retinal degenerative disorders (RDDs) in South Africa using exon 1 and 2 of RP2 in 20 unrelated families with an X-linked mode of retinal degenerative inheritance. Direct sequencing analysis revealed a C-->T transition at position 358 in the proband in a family of German origin. Subsequent analysis revealed that this Arg120stop mutation cosegregated with the disease in an additional affected family member. The nonsense mutation, Arg120stop, could not however, be detected in the somatic cells of the obligate carrier female. This, the first report of a germ line mutation for a family with RP, has many implications for genetic counseling of retinal degeneration (RD). To avoid inaccurate risk assessment for RP due to epigenetic events, such as the rare occurrence of germ line mosaicism, genetic counseling in families with XLRP should always be guided by molecular testing.     

Three novel mutations of the RPGR gene exon ORF15 in three Japanese families with X‐linked retinitis pigmentosa

We describe three new mutations in a recently identified exon, ORF15, of the retinitis pigmentosa GTPase regulator gene (RPGR) in three unrelated Japanese families (Families 1–3) with X‐linked retinitis pigmentosa (XLRP). The affected males had typical retinitis pigmentosa (RP), whereas the obligate carrier females showed a wide clinical spectrum, ranging from minor symptoms to severe visual disability. Some carrier females in Families 1 and 2 showed typical RP, most carriers manifested high myopia and astigmatism, and their corrected visual acuity was insufficient. They showed an impairment of cone function following the rod dysfunction and accompanied by refractive errors. Microsatellite analysis of Family 1 revealed that the RP in the family was linked to the RP3 locus. Although one patient in the family had no mutation in the previously published exons 1–19 including exon 15a, he had a single‐nucleotide insertion in exon ORF15 (g.ORF15 + 753–754 insG). Likewise, patients in Families 2 and 3 had two‐base insertion/deletion in the exon, i.e., g.ORF15 + 833–834delGG and g.ORF15 + 861–862insGG, respectively. These insertional/deletional mutations observed in the three families are all different and new, and are predicted to lead to a frameshift, resulting in a truncated protein. These findings may support the previous hypothesis that RPGR‐ORF15 is a mutational hot spot. © 2001 Wiley‐Liss, Inc.     

C1q enhances cone photoreceptor survival in a mouse model of autosomal recessive retinitis pigmentosa

Retinitis pigmentosa (RP) is a degenerative retinal disease involving progressive loss of rod and cone photoreceptor function. It represents the most common form of registered blindness among the working aged populations of developed countries. Given the immense genetic heterogeneity associated with this disease, parameters influencing cone photoreceptor survival (preservation of daytime vision) that are independent of primary mutations are exceedingly important to identify from a therapeutic standpoint. Here we identify C1q, the primary component of the classical complement pathway, as a cone photoreceptor neuronal survival factor.