Exome sequencing and analysis of induced pluripotent stem cells identify the cilia-related gene male germ cell-associated kinase (MAK) as a cause of retinitis pigmentosa
Retinitis pigmentosa (RP) is a genetically heterogeneous heritable disease characterized by apoptotic death of photoreceptor cells. We used exome sequencing to identify a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) as the cause of disease in an isolated individual wi...
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| Published in | Proceedings of the National Academy of Sciences - PNAS Vol. 108; no. 34; pp. E569 - E576 |
|---|---|
| Main Authors | , , , , , , , , |
| Format | Journal Article |
| Language | English |
| Published |
United States
National Academy of Sciences
23.08.2011
National Acad Sciences |
| Series | PNAS Plus |
| Subjects | |
| Online Access | Get full text |
| ISSN | 0027-8424 1091-6490 1091-6490 |
| DOI | 10.1073/pnas.1108918108 |
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| Abstract | Retinitis pigmentosa (RP) is a genetically heterogeneous heritable disease characterized by apoptotic death of photoreceptor cells. We used exome sequencing to identify a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) as the cause of disease in an isolated individual with RP. Screening of 1,798 unrelated RP patients identified 20 additional probands homozygous for this insertion (1.2%). All 21 affected probands are of Jewish ancestry. MAK encodes a kinase involved in the regulation of photoreceptor-connecting cilium length. Immunohistochemistry of human donor tissue revealed that MAK is expressed in the inner segments, cell bodies, and axons of rod and cone photoreceptors. Several isoforms of MAK that result from alternative splicing were identified. Induced pluripotent stem cells were derived from the skin of the proband and a patient with non-MAK–associated RP (RP control). In the RP control individual, we found that a transcript lacking exon 9 was predominant in undifferentiated cells, whereas a transcript bearing exon 9 and a previously unrecognized exon 12 predominated in cells that were differentiated into retinal precursors. However, in the proband with the Alu insertion, the developmental switch to the MAK transcript bearing exons 9 and 12 did not occur. In addition to showing the use of induced pluripotent stem cells to efficiently evaluate the pathogenicity of specific mutations in relatively inaccessible tissues like retina, this study reveals algorithmic and molecular obstacles to the discovery of pathogenic insertions and suggests specific changes in strategy that can be implemented to more fully harness the power of sequencing technologies. |
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| AbstractList | Retinitis pigmentosa (RP) is a genetically heterogeneous heritable disease characterized by apoptotic death of photoreceptor cells. We used exome sequencing to identify a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) as the cause of disease in an isolated individual with RP. Screening of 1,798 unrelated RP patients identified 20 additional probands homozygous for this insertion (1.2%). All 21 affected probands are of Jewish ancestry. MAK encodes a kinase involved in the regulation of photoreceptor-connecting cilium length. Immunohistochemistry of human donor tissue revealed that MAK is expressed in the inner segments, cell bodies, and axons of rod and cone photoreceptors. Several isoforms of MAK that result from alternative splicing were identified. Induced pluripotent stem cells were derived from the skin of the proband and a patient with non-MAK-associated RP (RP control). In the RP control individual, we found that a transcript lacking exon 9 was predominant in undifferentiated cells, whereas a transcript bearing exon 9 and a previously unrecognized exon 12 predominated in cells that were differentiated into retinal precursors. However, in the proband with the Alu insertion, the developmental switch to the MAK transcript bearing exons 9 and 12 did not occur. In addition to showing the use of induced pluripotent stem cells to efficiently evaluate the pathogenicity of specific mutations in relatively inaccessible tissues like retina, this study reveals algorithmic and molecular obstacles to the discovery of pathogenic insertions and suggests specific changes in strategy that can be implemented to more fully harness the power of sequencing technologies. Retinitis pigmentosa (RP) is a genetically heterogeneous heritable disease characterized by apoptotic death of photoreceptor cells. We used exome sequencing to identify a homozygous Alu insertion in exon 9 of male germ cell-associated kinase ( MAK ) as the cause of disease in an isolated individual with RP. Screening of 1,798 unrelated RP patients identified 20 additional probands homozygous for this insertion (1.2%). All 21 affected probands are of Jewish ancestry. MAK encodes a kinase involved in the regulation of photoreceptor-connecting cilium length. Immunohistochemistry of human donor tissue revealed that MAK is expressed in the inner segments, cell bodies, and axons of rod and cone photoreceptors. Several isoforms of MAK that result from alternative splicing were identified. Induced pluripotent stem cells were derived from the skin of the proband and a patient with non- MAK –associated RP (RP control). In the RP control individual, we found that a transcript lacking exon 9 was predominant in undifferentiated cells, whereas a transcript bearing exon 9 and a previously unrecognized exon 12 predominated in cells that were differentiated into retinal precursors. However, in the proband with the Alu insertion, the developmental switch to the MAK transcript bearing exons 9 and 12 did not occur. In addition to showing the use of induced pluripotent stem cells to efficiently evaluate the pathogenicity of specific mutations in relatively inaccessible tissues like retina, this study reveals algorithmic and molecular obstacles to the discovery of pathogenic insertions and suggests specific changes in strategy that can be implemented to more fully harness the power of sequencing technologies. Retinitis pigmentosa (RP) is a genetically heterogeneous heritable disease characterized by apoptotic death of photoreceptor cells. We used exome sequencing to identify a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) as the cause of disease in an isolated individual with RP. Screening of 1,798 unrelated RP patients identified 20 additional probands homozygous for this insertion (1.2%). All 21 affected probands are of Jewish ancestry. MAK encodes a kinase involved in the regulation of photoreceptor-connecting cilium length. Immunohistochemistry of human donor tissue revealed that MAK is expressed in the inner segments, cell bodies, and axons of rod and cone photoreceptors. Several isoforms of MAK that result from alternative splicing were identified. Induced pluripotent stem cells were derived from the skin of the proband and a patient with non-MAK-associated RP (RP control). In the RP control individual, we found that a transcript lacking exon 9 was predominant in undifferentiated cells, whereas a transcript bearing exon 9 and a previously unrecognized exon 12 predominated in cells that were differentiated into retinal precursors. However, in the proband with the Alu insertion, the developmental switch to the MAK transcript bearing exons 9 and 12 did not occur. In addition to showing the use of induced pluripotent stem cells to efficiently evaluate the pathogenicity of specific mutations in relatively inaccessible tissues like retina, this study reveals algorithmic and molecular obstacles to the discovery of pathogenic insertions and suggests specific changes in strategy that can be implemented to more fully harness the power of sequencing technologies. [PUBLICATION ABSTRACT] Retinitis pigmentosa (RP) is a genetically heterogeneous heritable disease characterized by apoptotic death of photoreceptor cells. We used exome sequencing to identify a homozygous Alu insertion in exon 9 of male germ cell-associated kinase ( MAK ) as the cause of disease in an isolated individual with RP. Screening of 1,798 unrelated RP patients identified 20 additional probands homozygous for this insertion (1.2%). All 21 affected probands are of Jewish ancestry. MAK encodes a kinase involved in the regulation of photoreceptor-connecting cilium length. Immunohistochemistry of human donor tissue revealed that MAK is expressed in the inner segments, cell bodies, and axons of rod and cone photoreceptors. Several isoforms of MAK that result from alternative splicing were identified. Induced pluripotent stem cells were derived from the skin of the proband and a patient with non- MAK –associated RP (RP control). In the RP control individual, we found that a transcript lacking exon 9 was predominant in undifferentiated cells, whereas a transcript bearing exon 9 and a previously unrecognized exon 12 predominated in cells that were differentiated into retinal precursors. However, in the proband with the Alu insertion, the developmental switch to the MAK transcript bearing exons 9 and 12 did not occur. In addition to showing the use of induced pluripotent stem cells to efficiently evaluate the pathogenicity of specific mutations in relatively inaccessible tissues like retina, this study reveals algorithmic and molecular obstacles to the discovery of pathogenic insertions and suggests specific changes in strategy that can be implemented to more fully harness the power of sequencing technologies. In summary, we have identified a cause of RP using a combination of next generation sequencing, single-strand conformation polymorphism analysis, and automated dideoxynucleotide sequencing of a large validation cohort, molecular analysis of patient-derived iPSCs, and molecular and histochemical analyses of human donor tissue. The discovery of a pathogenic insertion and the presence of a tissue-specific exon in the disease-causing gene suggest specific changes in strategy that can be implemented to better harness the power of sequencing technologies to identify mutations. The evidence that the insertion into exon 9 of MAK causes autosomal recessive RP is compelling. This variant was observed 43 times among 3,596 alleles of unrelated RP patients and was not observed among 5,904 alleles of unrelated individuals without photoreceptor disease; 42 of these alleles were observed among 21 homozygotes. Unaffected parents of these homozygotes are heterozygous for the insertion, whereas other unaffected first-degree relatives are either heterozygous or lack the insertion entirely. Analysis of iPSCs shows that the insertion in MAK results in the loss of a conserved retinal isoform. MAK is known to be involved in regulation of cilia length in photoreceptors, and its loss is known to cause photoreceptor death in mice ( 5 ). We next investigated the tissue distribution of MAK exon 12 in humans. The exon 12-containing transcript is only expressed in the retina. In contrast, all adult tissues studied except for smooth muscle express exon 9. When iPSC-derived retinal progenitor cells begin to express exon 9 at 33 d postdifferentiation, they also begin to express exon 12. Disruption of the developmental inclusion of exon 9 by the insertion resulted in the loss of exon 12. We then investigated the insertion's effect at the RNA and protein levels by using induced pluripotent stem cells (iPSCs) created from dermal fibroblasts of the proband homozygous for the insertion. These studies showed that the insertion seems to disrupt the correct splicing of a protein-coding region of the gene known as exon 9 ( Fig. P1 ), thereby preventing mature retinal cells from expressing the correct MAK isoform. Western blotting analysis revealed very little MAK protein in undifferentiated iPSCs. Because the cells differentiate into retinal precursors, the cell line derived from an RP control patient begins to express a MAK protein very similar in size to the protein seen in adult human retina. In contrast, iPSCs derived from the RP patient with the MAK insertion express a protein that is about 40 kDa smaller. MAK was localized to human retina using both monoclonal and polyclonal antibodies. In photoreceptor cells, labeling was predominately observed in the outer nuclear layer, axons, and inner segments. Outer segments did not show strong MAK expression. Immunolabeling with anti-MAK antibodies was identical with both monoclonal and polyclonal antibodies. The localization of MAK to photoreceptor cells was also observed in the cone photoreceptor cells located in the fovea, the small region in the center of the retina responsible for high-acuity vision. The inner segments of these cones as well as the axons of the corresponding interneurons were also strongly positive. We screened 277 unrelated individuals without eye disease (554 chromosomes) for this 353-bp insertion and failed to find a single instance of this mutation. Next, we screened 1,798 unrelated individuals with autosomal recessive RP and identified 21 homozygous individuals, 1 individual heterozygous for the insertion, and 2 individuals with heterozygous missense variants. A total of five unaffected first-degree relatives had samples in the collection available for study. None of these individuals were homozygous for the insertion. There was no known consanguinity among any of the kindred harboring the insertion, but all 21 families reported Jewish ancestry. Genomic DNA from a patient with autosomal recessive RP was sequenced on both Illumina and ABI sequencing instruments. The Illumina sequencing experiment yielded 71 million uniquely mapped paired-end sequences, with each end being 50 bp in length, whereas the ABI experiment yielded 157 million uniquely mapped single-end sequences, each being 50 bp in length. These sequences were aligned to the reference human genomic sequence ( 3 ). In both experiments, more than 20,000 sequence variations were detected. An average of 417 plausible disease-causing sequence variations, in an average of 405 genes, was identified by each sequencing platform. Three genes were predicted to have homozygous truncating mutations, which would result in a shortened nonfunctional protein, but none of these genes were confirmed to be homozygous by the automated dideoxynucleotide sequencing method. Similarly, two genes were each predicted to harbor two different truncating mutations; however, only one variant in each gene was confirmed by Sanger sequencing. There were five genes with one truncating and one missense variant, and of these 10 variants, only 4 variants were present in the data from both sequencers. The ABI dataset contained two mutations in the cilia-associated gene male germ cell-associated kinase ( MAK ) that were not present in the Illumina dataset. The MAK gene, which encodes the MAK enzyme, has been described as a testis-enriched gene with two transcripts that result in a complex pattern on Western blot. Despite its expression during the cell cycle in developing germ cells, targeted deletion of Mak in mice does not result in impaired fertility ( 4 ). In contrast, studies of the retina in Mak −/− mice reveal a dramatic effect of Mak deficiency on photoreceptor cell structure, function, and viability ( 5 ). Mice lacking Mak show elongated connecting cilia, reduced electrical response to light stimulation, protein mislocalization, and ultrastructural defects in outer segment morphogenesis ( 5 ). When we amplified exon 9, a protein-coding segment of the MAK gene, to confirm the above-mentioned variants, we observed a larger than expected fragment. Retinitis pigmentosa (RP) is a heritable eye disease characterized by the death of photoreceptor cells in the retina. It is estimated that mutations in more than 100 genes cause the disease ( 1 , 2 ); however, at present, less than one-half of the disease-causing genes have been identified ( 2 ). Many physicians envision the day when genomic sequence information from individual patients can be used routinely to facilitate their care. However, to achieve this goal, analytic methods and human genetic polymorphism databases will need to be developed to the degree that disease-causing mutations can be reliably detected. In this study, we show how next generation sequencing and stem cell technologies can be combined to identify disease-causing genes. Retinitis pigmentosa (RP) is a genetically heterogeneous heritable disease characterized by apoptotic death of photoreceptor cells. We used exome sequencing to identify a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) as the cause of disease in an isolated individual with RP. Screening of 1,798 unrelated RP patients identified 20 additional probands homozygous for this insertion (1.2%). All 21 affected probands are of Jewish ancestry. MAK encodes a kinase involved in the regulation of photoreceptor-connecting cilium length. Immunohistochemistry of human donor tissue revealed that MAK is expressed in the inner segments, cell bodies, and axons of rod and cone photoreceptors. Several isoforms of MAK that result from alternative splicing were identified. Induced pluripotent stem cells were derived from the skin of the proband and a patient with non-MAK-associated RP (RP control). In the RP control individual, we found that a transcript lacking exon 9 was predominant in undifferentiated cells, whereas a transcript bearing exon 9 and a previously unrecognized exon 12 predominated in cells that were differentiated into retinal precursors. However, in the proband with the Alu insertion, the developmental switch to the MAK transcript bearing exons 9 and 12 did not occur. In addition to showing the use of induced pluripotent stem cells to efficiently evaluate the pathogenicity of specific mutations in relatively inaccessible tissues like retina, this study reveals algorithmic and molecular obstacles to the discovery of pathogenic insertions and suggests specific changes in strategy that can be implemented to more fully harness the power of sequencing technologies.Retinitis pigmentosa (RP) is a genetically heterogeneous heritable disease characterized by apoptotic death of photoreceptor cells. We used exome sequencing to identify a homozygous Alu insertion in exon 9 of male germ cell-associated kinase (MAK) as the cause of disease in an isolated individual with RP. Screening of 1,798 unrelated RP patients identified 20 additional probands homozygous for this insertion (1.2%). All 21 affected probands are of Jewish ancestry. MAK encodes a kinase involved in the regulation of photoreceptor-connecting cilium length. Immunohistochemistry of human donor tissue revealed that MAK is expressed in the inner segments, cell bodies, and axons of rod and cone photoreceptors. Several isoforms of MAK that result from alternative splicing were identified. Induced pluripotent stem cells were derived from the skin of the proband and a patient with non-MAK-associated RP (RP control). In the RP control individual, we found that a transcript lacking exon 9 was predominant in undifferentiated cells, whereas a transcript bearing exon 9 and a previously unrecognized exon 12 predominated in cells that were differentiated into retinal precursors. However, in the proband with the Alu insertion, the developmental switch to the MAK transcript bearing exons 9 and 12 did not occur. In addition to showing the use of induced pluripotent stem cells to efficiently evaluate the pathogenicity of specific mutations in relatively inaccessible tissues like retina, this study reveals algorithmic and molecular obstacles to the discovery of pathogenic insertions and suggests specific changes in strategy that can be implemented to more fully harness the power of sequencing technologies. |
| Author | Tucker, Budd A Sheffield, Val C Jacobson, Samuel G Mullins, Robert F Scheetz, Todd E Stone, Edwin M Hoffmann, Jeremy M Johnston, Rebecca M DeLuca, Adam P |
| Author_xml | – sequence: 1 fullname: Tucker, Budd A – sequence: 2 fullname: Scheetz, Todd E – sequence: 3 fullname: Mullins, Robert F – sequence: 4 fullname: DeLuca, Adam P – sequence: 5 fullname: Hoffmann, Jeremy M – sequence: 6 fullname: Johnston, Rebecca M – sequence: 7 fullname: Jacobson, Samuel G – sequence: 8 fullname: Sheffield, Val C – sequence: 9 fullname: Stone, Edwin M |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/21825139$$D View this record in MEDLINE/PubMed |
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| Copyright | Copyright National Academy of Sciences Aug 23, 2011 |
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| Notes | SourceType-Scholarly Journals-1 ObjectType-Feature-1 content type line 14 ObjectType-Article-2 content type line 23 ObjectType-Article-1 ObjectType-Feature-2 Author contributions: B.A.T., T.E.S., R.F.M., V.C.S., and E.M.S. designed research; B.A.T., T.E.S., R.F.M., A.P.D., J.M.H., R.M.J., and E.M.S. performed research; B.A.T., T.E.S., R.F.M., S.G.J., and E.M.S. contributed new reagents/analytic tools; B.A.T., T.E.S., R.F.M., A.P.D., R.M.J., S.G.J., V.C.S., and E.M.S. analyzed data; and B.A.T., T.E.S., R.F.M., S.G.J., V.C.S., and E.M.S. wrote the paper. Edited by Jeremy Nathans, Johns Hopkins University, Baltimore, MD, and approved July 18, 2011 (received for review June 6, 2011) |
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| Snippet | Retinitis pigmentosa (RP) is a genetically heterogeneous heritable disease characterized by apoptotic death of photoreceptor cells. We used exome sequencing to... |
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| SubjectTerms | Alternative splicing Alu Elements - genetics Amino Acid Sequence ancestry Apoptosis Axons Biological Sciences Biomarkers - metabolism Cell body Cell Differentiation Cilia - genetics Cones cones (retina) death Donors Exons Exons - genetics Eye diseases Genealogy and Heraldry genes Humans Immunohistochemistry induced pluripotent stem cells Induced Pluripotent Stem Cells - metabolism Insertion Isoenzymes - metabolism Jews Jews - genetics Kinases Molecular Sequence Data Mutagenesis, Insertional - genetics Mutation Organ Specificity Pathogenicity Pathogens patients Photoreceptors PNAS Plus Point Mutation - genetics Protein Serine-Threonine Kinases - chemistry Protein Serine-Threonine Kinases - genetics Retina Retinal Cone Photoreceptor Cells - enzymology Retinal Cone Photoreceptor Cells - pathology Retinal Degeneration - complications Retinal Degeneration - enzymology Retinal Rod Photoreceptor Cells - enzymology Retinal Rod Photoreceptor Cells - pathology Retinitis pigmentosa Retinitis Pigmentosa - complications Retinitis Pigmentosa - enzymology Retinitis Pigmentosa - genetics screening sequence analysis Sequence Analysis, DNA Skin Stem cells Transcription |
| Title | Exome sequencing and analysis of induced pluripotent stem cells identify the cilia-related gene male germ cell-associated kinase (MAK) as a cause of retinitis pigmentosa |
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