Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR

Martı́nez-Mir, Amalia; Paloma, E; Allikmets, Rando; Ayuso, Carmen; T, Del Río; Dean, Michael; Vilageliu, Lluı̈sa; Gonzàlez‐Duarte, Roser; Balcells, Susana

doi:10.1038/ng0198-11

Cited by 342 publications

(201 citation statements)

References 12 publications

Supporting

Mentioning

190

Contrasting

Unclassified

Order By: Relevance

“…Many genes that cause nonsyndromic RP have also been associated with other retinal diseases such as Leber congenital amaurosis (LCA), Bardet Biedl syndrome (BBS), Usher syndrome, cone rod dystrophy, and Stargardt disease (3,(16)(17)(18)(19). To investigate the possibility that the Alu insertion in MAK is also involved in any of these phenotypes, we screened 454 probands with LCA, 125 probands with BBS, 109 probands with Usher syndrome, 175 probands with cone rod dystrophy, and 202 probands with Stargardt disease.…”

Section: Alu Insertion In Mak Is Not Associated With Other Photoreceptormentioning

confidence: 99%

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

Tucker

Scheetz

Mullins

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

190

191

View full text Add to dashboard Cite

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.

show abstract

Section: Alu Insertion In Mak Is Not Associated With Other Photoreceptormentioning

confidence: 99%

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

Tucker

Scheetz

Mullins

et al. 2011

Proc. Natl. Acad. Sci. U.S.A.

190

191

View full text Add to dashboard Cite

show abstract

“…Mutations in a photoreceptor-specific ATP-binding cassette transporter gene, ABCA4, have been implicated in patients with autosomal recessive Stargardt disease (STGD), 1 ± 10 cone-rod dystrophy 6,10 ± 12 and retinitis pigmentosa. 11,13,14 Moreover, heterozygous ABCA4 mutations have been associated with an increased susceptibility to age-related macular dystrophy, a multifactorial disorder that frequently affects the elderly. 15 ± 17 To explain how mutations in a single gene give rise to a spectrum of different phenotypes, a model has been proposed that correlates the severity of the retinal dystrophy with the severity of the mutations and the residual activity of the ABCR protein.…”

Section: Introductionmentioning

confidence: 99%

“…15 ± 17 To explain how mutations in a single gene give rise to a spectrum of different phenotypes, a model has been proposed that correlates the severity of the retinal dystrophy with the severity of the mutations and the residual activity of the ABCR protein. 4,5,11,13,18,19 ABCA4 is specifically expressed in cone and rod photoreceptor outer segments, 1,20 where it is thought to act as a Nretinylidene-phosphatidylethanolamine flippase, 21,22 moving all-trans-retinal from the lumenal to the cytosolic side of the discs.…”

Section: Introductionmentioning

confidence: 99%

The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe

Maugeri¹,

Flothmann

Hemmrich

et al. 2002

Eur J Hum Genet

Self Cite

View full text Add to dashboard Cite

Inherited retinal dystrophies represent the most important cause of vision impairment in adolescence, affecting approximately 1 out of 3000 individuals. Mutations of the photoreceptor-specific gene ABCA4 (ABCR) are a common cause of retinal dystrophy. A number of mutations have been repeatedly reported for this gene, notably the 2588G4C mutation which is frequent in both patients and controls. Here we ascertained the frequency of the 2588G4C mutation in a total of 2343 unrelated random control individuals from 11 European countries and 241 control individuals from the US, as well as in 614 patients with STGD both from Europe and the US. We found an overall carrier frequency of 1 out of 54 in Europe, compared with 1 out of 121 in the US, confirming that the 2588G4C ABCA4 mutation is one of the most frequent autosomal recessive mutations in the European population. Carrier frequencies show an increasing gradient in Europe from South-West to North-East. The lowest carrier frequency, 0 out of 199 (0%), was found in Portugal; the highest, 11 out of 197 (5.5%), was found in Sweden. Haplotype analysis in 16 families segregating the 2588G4C mutation showed four intragenic polymorphisms invariably present in all 16 disease chromosomes and sharing of the same allele for several markers flanking the ABCA4 locus in most of the disease chromosomes. These results indicate a single origin of the 2588G4C mutation which, to our best estimate, occurred between 2400 and 3000 years ago.European Journal of Human Genetics (2002) 10, 197 ± 203 ã 2002 Nature Publishing Group All rights reserved 1018-4813/02 $25.00 www.nature.com

show abstract

“…Tangier disease -Defect in cholesterol transport between liver and other tissues [2][3][4][5]. Stargardt disease -Abnormal accumulation of retinoid [6][7][8]. Neu-Laxova syndrome -Autosomal recessive disorder with severe IUGR, extreme microcephaly, ichthyosis, marked edema with skin restriction, cranio facial anomalies, limb deformities and CNS malformations.…”

Section: Differential Diagnosismentioning

confidence: 99%

Expecting the most unexpected – a harlequin baby! A case report and literature analysis

Srinivasan¹

2012

Our Dermatol Online

View full text Add to dashboard Cite

Retinitis pigmentosa caused by a homozygous mutation in the Stargardt disease gene ABCR

Cited by 342 publications

References 12 publications

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

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

The ABCA4 2588G>C Stargardt mutation: single origin and increasing frequency from South-West to North-East Europe

Expecting the most unexpected – a harlequin baby! A case report and literature analysis

Contact Info

Product

Resources

About