Joubert Syndrome 2 (JBTS2) in Ashkenazi Jews Is Associated with a TMEM216 Mutation

Edvardson, Simon; Shaag, Avraham; Zenvirt, Shamir; Erlich, Yaniv; Hannon, Gregory J.; Shanske, Alan; Gomori, John M.; Ekstein, Joseph; Elpeleg, Orly

doi:10.1016/j.ajhg.2009.12.007

Cited by 91 publications

(73 citation statements)

References 19 publications

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“…AHI1 is highly conserved throughout evolution and encodes the Ahi1 protein (also known as Jouberin) [9]. By performing a detailed in silico search of proteomes of eukaryotic organisms, we have now identified additional homologues, confirming a conserved role for this gene between ciliated protozoa and man.…”

Section: Introductionmentioning

confidence: 79%

“…l A transverse section of a 48 hpf embryo following in situ hybridization with ahi1 probe, demonstrates expression of ahi1 in the distal pronephros (white arrows). NC notochord; S somites mutations, with a preponderance towards central nervous system defects, and milder renal phenotypes [4,9,[23][24][25][26]. A mismatch control morpholino (mmMO) had no effect on nervous system development or renal cyst formation (Fig.…”

Section: Ahi1 Encodes a Ciliary/basal Body Protein Which Is Highly Comentioning

confidence: 99%

“…Similarly, the relative risk (RR) of a retinal defect (such as retinal dystrophy) associated with nephronophthisis was significantly increased (RR = 7.5; 95% CI 4.0-11.2) in the presence of the R830W AHI1 mutation [26]. Early expression (from embryonic day 10.5) of Ahi1 is seen in murine brain, which persists into adulthood [9]. Previous work using zebrafish embryos aged 2.5-5 days post-fertilization has documented an expression pattern for ahi1 in the brain (olfactory bulb, telencephalon, diencephalon, tectum, and cerebellum) and retina [29].…”

Section: Introductionmentioning

confidence: 98%

“…These include JBTS types 1-11: INPP5E [8], TMEM216 [9], AHI1 [4,9], NPHP1 [11], CEP290 [12][13][14], TMEM67 [15,16], RPGRIP1L [5], ARL13B [17], CC2D2A [18], CXORF5 [19] and TCTN2 [22]. The protein products encoded by all of these genes have been localized in the primary cilium [20], a highly conserved cellular organelle, central to the regulation of cellular signaling pathways [21].…”

Section: Introductionmentioning

confidence: 99%

“…Mutations in AHI1 (Abelson-helper integration site-1) are a common genetic cause of JBTS, accounting for 12% of cases, and 20% of individuals with JBTS and Leber's congenital amaurosis [9,[23][24][25][26]. AHI1 is highly conserved throughout evolution and encodes the Ahi1 protein (also known as Jouberin) [9].…”

Section: Introductionmentioning

confidence: 99%

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Modelling a ciliopathy: Ahi1 knockdown in model systems reveals an essential role in brain, retinal, and renal development

Simms

Hynes

Eley

et al. 2011

Cell. Mol. Life Sci.

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Joubert syndrome and related diseases (JSRD) are cerebello-oculo-renal syndromes with phenotypes including cerebellar hypoplasia, retinal dystrophy, and nephronophthisis (a cystic kidney disease). Mutations in AHI1 are the most common genetic cause of JSRD, with developmental hindbrain anomalies and retinal degeneration being prominent features. We demonstrate that Ahi1, a WD40 domain-containing protein, is highly conserved throughout evolution and its expression associates with ciliated organisms. In zebrafish ahi1 morphants, the phenotypic spectrum of JSRD is modeled, with embryos showing brain, eye, and ear abnormalities, together with renal cysts and cloacal dilatation. Following ahi1 knockdown in zebrafish, we demonstrate loss of cilia at Kupffer's vesicle and subsequently defects in cardiac left-right asymmetry. Finally, using siRNA in renal epithelial cells we demonstrate a role for Ahi1 in both ciliogenesis and cell-cell junction formation. These data support a role for Ahi1 in epithelial cell organization and ciliary formation and explain the ciliopathy phenotype of AHI1 mutations in man.

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Section: Introductionmentioning

confidence: 79%

Section: Ahi1 Encodes a Ciliary/basal Body Protein Which Is Highly Comentioning

confidence: 99%

Section: Introductionmentioning

confidence: 98%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Modelling a ciliopathy: Ahi1 knockdown in model systems reveals an essential role in brain, retinal, and renal development

Simms

Hynes

Eley

et al. 2011

Cell. Mol. Life Sci.

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Prolonged Pursuit by Optokinetic Drum Testing in Asymptomatic Female Carriers of Novel <emph type="ital">FRMD7</emph> Splice Mutation c.1050 +5 G>A

Khan

Shinwari²,

Al-Sharif³

et al. 2011

Arch Ophthalmol

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To determine the genotype underlying suspected X-linked infantile nystagmus in a family and to correlate genotype with clinical examination in potential female carriers. Methods: Ophthalmic examination (ophthalmic, orthoptic, optokinetic [OKN] drum, and electrophysiologic when possible) and candidate gene analysis. Results: Two affected brothers had infantile nystagmus with no evidence of associated visual or neurological disease. The symptomatic maternal aunt had infantile nystagmus in addition to congenital fibrosis of the extraocular muscles (CFEOM) (bilateral hypotropia, exotropia, ptosis, almost complete ophthalmoplegia, and poorly reactive pupils). A sister, the mother, and the maternal grandmother-all 3 of whom were asymptomatichad delayed corrective saccades (prolonged pursuit) during OKN drum testing. A brother and the father-both of whom were asymptomatic-had unremarkable examination findings. A FRMD7 splice variant (c.1050ϩ5 GϾA) was identified in the 2 affected brothers and in the 3 asymptomatic women only. Allele sharing analysis further confirmed that the aunt's phenotype was not related to the FRMD7 variant, which was absent in 246 ethnic controls. Her phenotype was also not related to mutation in known CFEOM genes (KIF21A, PHOX2A, TUBB3). Conclusions: Prolonged pursuit responses during OKN drum testing in asymptomatic female carriers is consistent with the concept of infantile nystagmus being an abnormally increased pursuit oscillation. Further studies are required to determine the reproducibility of this potential female carrier sign. Rather than being FRMD7 related, nystagmus in the maternal aunt represented a second disease in this family, likely related to CFEOM. Clinical Relevance: Clinicians can use the OKN drum to assess obligate female carriers in a family suspected of having X-linked nystagmus.

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Identification of Variants in <emph type="ital">CNGA3</emph> as Cause for Achromatopsia by Exome Sequencing of a Single Patient

Lam¹

2011

Arch Ophthalmol

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To report disease-causing mutations in the cyclic nucleotide-gated channel ␣ 3 gene (CNGA3) identified by exome sequencing and bioinformatics filtering in a single patient. Methods: The entire protein-coding sequence of a patient with a retinal disease was enriched by in-solution targeted capture and massively parallel sequenced at 50fold coverage. The assembled sequence was compared with databases of normal genomic sequences to identify nonsynonymous variants, which were further filtered (1) with a prioritization of genes associated with retinal diseases, (2) according to the likelihood of variant damage to protein function, (3) following the predictions of a recessive model, and (4) against common polymorphisms observed in normal genomes. Clinical evaluation and segregation analysis of the mutant alleles in the patient's family were performed; mutations were excluded in healthy controls. Results: Analysis yielded a molecular diagnosis of achromatopsia. Two compound heterozygous mutations were identified in CNGA3 of this patient, c.829CϾT p.R277C and c.1580TϾG p.L527R; they were not observed in the normal population and cosegregated with the phenotype of achromatopsia in the patient's family. Conclusion: These mutations are the cause of achromatopsia in this family. Clinical Relevance: The key advantages of massively parallel sequencing over linkage mapping and cloning are highlighted by (1) the small sample size required for successful analysis and (2) the rapid and highthroughput manner in which the mutations are identified. This new tool will likely have major effects on the management and research of rare genetic eye diseases in the new era of personalized genomic medicine.

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Joubert Syndrome 2 (JBTS2) in Ashkenazi Jews Is Associated with a TMEM216 Mutation

Cited by 91 publications

References 19 publications

Modelling a ciliopathy: Ahi1 knockdown in model systems reveals an essential role in brain, retinal, and renal development

Modelling a ciliopathy: Ahi1 knockdown in model systems reveals an essential role in brain, retinal, and renal development

Prolonged Pursuit by Optokinetic Drum Testing in Asymptomatic Female Carriers of Novel <emph type="ital">FRMD7</emph> Splice Mutation c.1050 +5 G>A

Identification of Variants in <emph type="ital">CNGA3</emph> as Cause for Achromatopsia by Exome Sequencing of a Single Patient

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Joubert Syndrome 2 (JBTS2) in Ashkenazi Jews Is Associated with a TMEM216 Mutation

Cited by 91 publications

References 19 publications

Modelling a ciliopathy: Ahi1 knockdown in model systems reveals an essential role in brain, retinal, and renal development

Modelling a ciliopathy: Ahi1 knockdown in model systems reveals an essential role in brain, retinal, and renal development

Prolonged Pursuit by Optokinetic Drum Testing in Asymptomatic Female Carriers of Novel <emph type="ital">FRMD7</emph> Splice Mutation c.1050 +5 G&gt;A

Identification of Variants in <emph type="ital">CNGA3</emph> as Cause for Achromatopsia by Exome Sequencing of a Single Patient

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Prolonged Pursuit by Optokinetic Drum Testing in Asymptomatic Female Carriers of Novel <emph type="ital">FRMD7</emph> Splice Mutation c.1050 +5 G>A