Genetic Basis of Nanophthalmos and Human Ocular Biometry

纳米眼球的遗传基础和人类眼部生物测定

基本信息

批准号：
7924087
负责人：
Olof H Sundin
金额：
$ 36.98万
依托单位：
TEXAS TECH UNIVERSITY HEALTH SCIS CENTER
依托单位国家：
美国
项目类别：
财政年份：
2001
资助国家：
美国
起止时间：
2001-08-15 至 2012-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/7924087
关键词：
11q23.3 Adult Affect Alleles Amish Angle-Closure Glaucoma Anterior Asians Binding Biometry Blindness Ciliary Body Cornea Cysteine-Rich Domain DNA Diagnosis Disease Elements Exhibits Exons Eye Eye Development Family Foundations Founder Effect Frameshift Mutation Funding General Population Genes Genetic Genetic Variation Genomics Genotype Greek Hereditary Disease Heterozygote Human Hyperopia Image Inbred Strain Inherited Integral Membrane Protein Introns Length Measures Mennonite Microphthalmos Modeling Mus Mutation Neurologic Online Mendelian Inheritance In Man Optics Parents Patients Peptide Hydrolases Phenotype Physiological Play Population Primary Angle Closure Glaucoma Proteins Quantitative Trait Loci Relative (related person)Retina Retinal Detachment Role SNP genotyping Shapes Siblings Structure Structure of retinal pigment epithelium Testing Therapeutic Intervention Variant Vertebrate Photoreceptors Visual Visual Acuity Widespread Disease Work anterior chamber base disability effective therapy gene function high risk kindred lens macular edema member mutant novel null mutation photoreceptor degeneration postnatal proband public health relevance receptor trait

项目摘要

DESCRIPTION (provided by applicant): Nanophthalmos is a rare genetic disorder in which both eyes are well formed, but have unusually short axial lengths. Extreme hyperopia, from +8 to +25 diopters, occurs because the image-forming cornea and lens are too close to the retina. As adults, nanophthalmos patients often develop major secondary complications, including angle closure glaucoma, macular edema and exudative retinal detachment. During the first funding period of EY013610 we discovered the novel NN02 locus at 11q23.3, and identified null mutations in MFRP as the cause of nanophthalmos (OMIM 609549). MFRP encodes an integral membrane protein expressed at significant levels only in the ciliary body and retinal pigment epithelium (RPE). It is a protein of unknown function that includes four globular domains with homology to non-catalytic elements of the Tolloid proteases, and a single domain homologous to the Wnt-binding portion of the Frizzled receptor. Patients completely lacking MFRP function have axial lengths ranging from 15.4 to 16.3 mm, relative to the population average of 23.5 mm. Lens-corrected visual acuity varies from 20/20 to 20/200, and physiological tests demonstrate that this gene is not essential for the basic function of rods and cones. No neurological or other anomalies are apparent, indicating that the required functions of MFRP are highly eye-specific. The gene does not appear to play the same role in ocular development of the mouse. A mutation in mouse Mfrp causes postnatal photoreceptor degeneration but does not affect ocular size. Out of 28 families, we have identified MFRP null mutations in all 4 recessive families. No mutations were identified in the one family exhibiting dominant inheritance, or in the 23 sporadic patients. For the second funding period we propose to identify severe and hypomorphic mutant alleles of MFRP that exist in the population and to determine their phenotypic effect. We will determine whether common genetic variation in MFRP acts as a quantitative trait in the families of sporadic nanophthalmos patients. We will also determine whether genetic variation in MFRP has the potential to govern axial length and anterior chamber depth in the general population. If we can establish that such genetic variation contributes to human ocular biometry, this would provide an essential basis and rationale for any therapeutic interventions involving the function of this gene. PUBLIC HEALTH RELEVANCE: Nanophthalmos is a rare, inherited form of extreme farsightedness that often progresses to angle closure glaucoma, retinal detachment and blindness. It is one of the best Mendelian models for primary angle closure glaucoma, a major cause of severe visual disability, especially in populations of Indian or Asian descent. The identification of common gene variants of MFRP that alter ocular shape and predispose the eye to angle closure glaucoma promises to further our understanding of the origins of this widespread disease, and to provide a foundation for developing more effective treatment.

描述（由申请人提供）：纳米植物是一种罕见的遗传疾病，两只眼睛都形成得很好，但轴向长度异常短。极端的远视，从+8到+25二极管，是因为形成图像的角膜和镜头太近的视网膜。作为成年人，纳米恐怖分子患者经常会出现主要的继发并发症，包括角度闭合青光眼，黄斑水肿和渗出性视网膜脱离。在EY013610的第一个资金期间，我们在11q23.3发现了新的NN02基因座，并将MFRP中的无效突变确定为纳米骨骼的原因（OMIM 609549）。 MFRP编码仅在睫状体和视网膜色素上皮（RPE）中以显着水平表达的整体膜蛋白。它是一种未知功能的蛋白质，其中包括四个与Toloid蛋白酶的非催化元素同源的球状结构域，以及与毛百怪受体的WNT结合部分同源的单个结构域。完全缺乏MFRP功能的患者的轴向长度范围为15.4至16.3 mm，相对于人口平均值为23.5 mm。透镜校正的视力从20/20到20/200不等，生理测试表明，该基因对于杆和锥的基本功能并不是必不可少的。没有明显的神经系统或其他异常，表明MFRP的所需功能是高度特异性的。该基因似乎在小鼠的眼部发育中起着相同的作用。小鼠MFRP中的突变会导致产后光感受器变性，但不会影响眼部大小。在28个家庭中，我们已经确定了所有4个隐性家庭中的MFRP无效突变。在一个表现出主导遗传的家族中或23名零星患者中未发现突变。在第二个资金期间，我们建议确定人口中存在的MFRP的严重和肌型突变等位基因，并确定其表型效应。我们将确定MFRP中常见的遗传变异是否是零星纳米恐惧症患者家族的定量性状。我们还将确定MFRP的遗传变异是否有可能控制一般人群的轴向长度和前腔深度。如果我们能够确定这种遗传变异有助于人眼生物特征，这将为任何涉及该基因功能的治疗干预措施提供基本的基础和理由。公共卫生相关性：纳米植物是一种罕见的，遗传的极端远视形式，通常会发展为角度闭合青光眼，视网膜脱离和失明。它是孟德尔闭合青光眼的最佳门德尔模型之一，这是严重视觉障碍的主要原因，尤其是在印度或亚洲血统的种群中。 MFRP的常见基因变异的鉴定，这些变体改变了眼部形状和倾向于角度闭合青光眼，有望进一步了解我们对这种广泛疾病的起源的理解，并为开发更有效的治疗提供了基础。

项目成果

期刊论文数量（5）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Efficacy of topical dorzolamide therapy for cystoid macular edema in a patient with MFRP-related nanophthalmos-retinitis pigmentosa-foveoschisis-optic disk drusen syndrome.

DOI：
10.1097/icb.0000000000000088
发表时间：
2015
期刊：
Retinal cases & brief reports
影响因子：
0
作者：
Zacharias LC;Susanna R Jr;Sundin O;Finzi S;Susanna BN;Takahashi WY
通讯作者：
Takahashi WY

Novel membrane frizzled-related protein gene mutation as cause of posterior microphthalmia resulting in high hyperopia with macular folds.

新型膜卷曲相关蛋白基因突变导致后小眼球，导致高度远视并伴有黄斑皱襞。

DOI：
10.1111/aos.12105
发表时间：
2014
期刊：
Acta ophthalmologica
影响因子：
3.4
作者：
Wasmann,RosemarieA;Wassink-Ruiter,JolienSKlein;Sundin,OlofH;Morales,Elisa;Verheij,JokeBGM;Pott,JanWillemR
通讯作者：
Pott,JanWillemR

The human jejunum has an endogenous microbiota that differs from those in the oral cavity and colon.

DOI：
10.1186/s12866-017-1059-6
发表时间：
2017-07-17
期刊：
BMC microbiology
影响因子：
4.2
作者：
Sundin OH;Mendoza-Ladd A;Zeng M;Diaz-Arévalo D;Morales E;Fagan BM;Ordoñez J;Velez P;Antony N;McCallum RW
通讯作者：
McCallum RW