Preserving the Precious Gift of Sight

Rui Chen, PhD

MANNING RESEARCH PROJECT

Molecular and Human Genetics

Baylor College of Medicine

Houston, TX

 

Dr. Chen’s Research Project

Identification and Functional Analysis of Gene Involved in Retina Diseases and Development
 

Current Research Interests

To date, a total of 256 genes have been identified that are associated with heritable human eye diseases. Therefore, understanding of molecular mechanisms of retina disease is an essential first step for designing personalized treatments of eye diseases. The goal of this project is to identify novel genes involved in human retinal disorders, conduct functional analysis, and develop therapy of these disease genes using model organism such as Mus musculus.

Progress in 2016

Dr. Chen has completed the sequencing for all Saudi patient cohort as well as the 600 LCA patients from other collaborators. He is currently in the process of sequencing patients from Iran and the newly recruited 300 samples. Through exome sequencing, Dr. Chen has identified two novel LCA and RP disease genes in the past year, including CEP78 and RCBTB2. In addition, animal models have been generated for some of these newly discovered disease genes, for which functional studies are underway. This project provides benefits for the patients in several ways, such as when positive results were obtained the molecular mutation screen result provides critical information for diagnosis, prognosis, and potential treatment.

Plans for 2017

In this proposal, Dr. Chen will focus on identification of additional genes whose mutations cause LCA, the most common hereditary cause of visual impairment in infants and children. LCA shares common mechanisms with other retinal degenerative diseases. It has been estimated that mutations in known LCA genes account for about 70% of all cases. To clone additional LCA disease genes, his lab has collected DNA samples from 38 consanguineous geographically distinctive recessive families as well as 800 sporadic LCA cases. Dr. Chen will perform exome sequencing to identify the underlying mutations carried by this large collection. Results obtained from these experiments are likely to assist the development of new diagnostic tools and treatments, and provide important insights into the molecular mechanisms underlying LCA and retinal dystrophies in general. In parallel, Dr. Chen will develop potential therapeutic approach using the disease animal models established in his laboratory. Specific Aims: 1) Identify novel LCA disease genes; 1a) Whole exome sequencing of all consanguineous LCA families and sporadic cases; 1b) Next Generation sequencing data analysis to identify potential mutations; 1c) Confirmation of disease-specific mutations; 2) Functional analysis of candidate disease genes.

 Progress in 2015

1) Identify novel retina disease gene – Dr. Chen has completed the sequencing for all Saudi patient cohort as well as the 600 LCA patients from other collaborators. Initial analysis has been done for these patients, and he has identified several candidate novel disease genes. 2) Functional analysis of candidate disease genes – Through exome sequencing, Dr. Chen has identified several novel LCA and RP disease genes, such as ATF6 and CLAUP1. He has performed functional studies of these novel disease genes using both cell and animal model. Currently, Dr. Chen’s lab is in the process of generating mouse model for these disease genes, which will allow for additional mechanistic studies and developing therapeutic method of the disease.

Progress in 2014

The goal of Dr. Chen’s project is to identify novel genes involved in human retinal disorders, conduct functional analysis, and develop therapy of these disease genes using model organism such as Mus musculus. He has completed the sequencing for a Saudi patient cohort as well as more than 400 Leber congenital amaurosis (LCA) and retinitis pigmentosa (RP) patients with various ethnic backgrounds. Through exome sequencing and functional studies, Dr. Chen has identified several novel LCA and RP disease genes, such as HK1 and ATF6. This work has been accepted for publication in IOVS. Further analysis of this dataset is ongoing.

Progress in 2013

Dr. Chen has collected DNA samples from 38 consanguineous families with recessive Leber congenital amaurosis (LCA) as well as 800 sporadic cases in order to clone additional LCA disease genes. His laboratory has applied the cutting edge sequencing technology in cloning disease genes underlying LCA and performed whole exome sequencing on a large cohort of LCA patients. They have identified several novel mutation and candidate novel disease genes for which validation and functional analysis is currently underway.

Progress in 2012

Dr. Chen’s laboratory successfully cloned the LCA3 disease gene. To better understand its normal function in the retina, Dr. Chen examined the expression pattern of Spata7 in the developing and mature mouse retina and found that LCA3 is expressed in multiple layers, most strongly in the inner segment of photoreceptor cells. Results suggest a novel disease mechanism of LCA in which LCA3 functions as part of the protein transporter vesicle, potentially as a cargo receptor, in photoreceptor cells function. Significant progress was made on experiments identifying additional LCA disease genes. Exome sequencing of 110 isolated LCA patients has been completed and analysis of these data is ongoing.

Dr. Chen’s focus is on identification of additional genes whose mutations cause Leber congenital amaurosis (LCA), the most common hereditary cause of visual impairment in infants and children. To clone additional LCA disease genes, his laboratory has collected DNA samples from 38 consanguineous families with recessive LCA as well as 200 sporadic cases. Exome sequencing is performed for these samples to identify novel genes, which assists the development of new diagnostic tools and treatments.

In parallel, they study of the function of the POU-domain subfamily 6 genes during normal retinal development. Characterization of the function of this important gene subfamily will provide the basis toward creating new tools for both early diagnosis of individuals at work and developing reagents for treatment of retinal disease, including gene therapy.

Protein aggregation assay in cell culture for NMNAT1 mutant allele

Progress in 2011

Dr. Chen’s laboratory has applied the cutting edge sequencing technology in cloning disease genes underlying LCA and performed whole exome sequencing on 50 patients.  Based on their preliminary results, they have identified three novel LCA/RP disease genes, including CEP164, KCNJ13 and NMNAT1.

Results suggest a novel disease mechanism of LCA in which LCA3 functions as part of the protein transporter vesicle, potentially as a cargo receptor, in photoreceptor cells function. Dr. Chen has made significant progress in identifying additional LCA disease genes through exome sequencing.

Leber congenital amaurosis (LCA) is one of the most common hereditary causes of visual impairment in infants and children, which accounts for more than 5% of all retinal dystrophies.  The clinical phenotype of LCA can be extremely severe and it is characterized by several visual perturbations identifiable at birth or within the first year of life, including infantile nystagmus, a variety of fundus changes, and minimal or absent responses on the electroretinogram, each of which occurs with an autosomal recessive mode of inheritance.

In Dr. Chen’s project, his laboratory aims to identify the underlying mutations for LCA, which is the essential first step for understanding the molecular mechanisms and designing proper treatment for this disease.

Based on homozygosity mapping of all the consanguineous LCA families with no known mutations (Li et al., 2009), Dr. Chen’s laboratory had identified numerous LCA disease candidate loci. In total, they have completed homozygosity mapping for 23 LCA families, each containing homozygous regions which range in size from 2 Mb to more than 200 Mb. Among them, candidate loci from five families, KKESH008, KKESH012, KKESH013, KKESH086, and KKESH205 are less than 10 Mb in size. In addition, candidate loci from two families, KKESH038 and KKESH050, are between 10-20 Mb in size. Furthermore, candidate loci from seven families are greater than 20 Mb but below 100 Mb in size. Finally, candidate loci from ten families are greater than 100 Mb in size with the largest at 243 Mb.

Whole exome capture sequencing has been performed on the first 15 families.  Very interestly, mutations in previous known retinal disease genes, including BBS4, MyoA, and NPHP5, and  have been identified in these families.  Since patients in this family do not display other symptom associated with mutations in these genes, these results provide new link between these syndromic retinal disease genes to non syndromic LCA, an emerging theme that have been observed recently by several groups.  Furthermore, Dr. Chen has identified several novel candidate LCA disease genes, including CEP164.  Further evaluation of these novel disease genes are currently underway.

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The mission of the Retina Research Foundation is to reduce retinal blindness worldwide by funding programs in research and education. As a public charity, RRF raises funds from the private sector and the investment of its endowment funds.

RRF’s 48th Anniversary

October 1, 2017