Precise Genetic Mapping and Haplotype Analysis of the Familial Dysautonomia Gene on Human Chromosome 9q31

Blumenfeld, Anat; Slaugenhaupt, Susan A.; Liebert, Christopher B.; Temper, Violeta; Maayan, Channa; Gill, Sandra; Lucente, Diane; Idelson, Maria; MacCormack, Kathy; Monahan, Mary Anne; Mull, James; Leyne, Maire; Mendillo, Marc L.; Schiripo, Taryn A.; Mishori, Esther; Breakefield, Xandra O.; Axelrod, Felicia B.; Gusella, James F.

doi:10.1086/302339

Cited by 66 publications

(44 citation statements)

References 36 publications

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“…The identification of mutations in the IKBKAP gene in FD patients was a critical first step in the endeavor to find a treatment for FD (4,7,41). As a result of this discovery, it became clear that cellular levels of IKAP are diminished in a tissue-specific manner due to the IVS20ϩ6TϾC mutation, with the lowest levels observed in the nervous system.…”

Section: Discussionmentioning

confidence: 99%

Loss of Mouse Ikbkap, a Subunit of Elongator, Leads to Transcriptional Deficits and Embryonic Lethality That Can Be Rescued by Human IKBKAP

Chen

Hims

Shetty

et al. 2009

Molecular and Cellular Biology

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107

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Familial dysautonomia (FD), a devastating hereditary sensory and autonomic neuropathy, results from an intronic mutation in the IKBKAP gene that disrupts normal mRNA splicing and leads to tissue-specific reduction of IKBKAP protein (IKAP) in the nervous system. To better understand the roles of IKAP in vivo, an Ikbkap knockout mouse model was created. Results from our study show that ablating Ikbkap leads to embryonic lethality, with no homozygous Ikbkap knockout (Ikbkap ؊/؊ ) embryos surviving beyond 12.5 days postcoitum. Morphological analyses of the Ikbkap ؊/؊ conceptus at different stages revealed abnormalities in both the visceral yolk sac and the embryo, including stunted extraembryonic blood vessel formation, delayed entry into midgastrulation, disoriented dorsal primitive neural alignment, and failure to establish the embryonic vascular system. Further, we demonstrate downregulation of several genes that are important for neurulation and vascular development in the Ikbkap ؊/؊ embryos and show that this correlates with a defect in transcriptional elongation-coupled histone acetylation. Finally, we show that the embryonic lethality resulting from Ikbkap ablation can be rescued by a human IKBKAP transgene. For the first time, we demonstrate that IKAP is crucial for both vascular and neural development during embryogenesis and that protein function is conserved between mouse and human.IKBKAP (encoding IB kinase-associated protein, also called Elongator protein 1) is the gene mutated in hereditary sensory and autonomic neuropathy type III, or familial dysautonomia (FD). All FD patients carry at least one copy of a splicing mutation in IKBKAP, which causes aberrant exon skipping and subsequent tissue-specific reduction of protein expression in FD patients (1,41,42). The IKBKAP gene is highly conserved across species, with the human and mouse proteins (IKAP and Ikap, respectively) sharing more than 80% amino acid homology (12). The IKBKAP protein, IKAP, was first reported to act as a scaffolding protein for the IB kinase complex (11). Recent studies, however, have shown that IKAP does not play a role in NF-B (nuclear factor B) signaling, but rather, it is a subunit of the human Elongator complex, which is important for efficient transcriptional elongation (19,28,36).FD (or Riley-Day syndrome) is one of the best known recessive hereditary neuropathies, with an extremely high carrier frequency in the Ashkenazi Jewish population, which ranges from 1 in 17 to 1 in 28 depending on the country of origin (29,33,42). Clinical characteristics of FD include diminished tear secretion, dysphagia, esophageal and gastric dysmotility, gastroesophageal reflux, spinal curvature, postural hypotension, blotching, excessive sweating, and decreased deep-tendon reflexes (2). Fatality in FD patients is high, and only half survive to 40 years of age. Clinical reports have shown that the failure of autonomic function is one of the major causes of death (21). To date, three FD-causing mutations have been identified in the IKBKAP gene: a...

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Section: Discussionmentioning

confidence: 99%

Loss of Mouse Ikbkap, a Subunit of Elongator, Leads to Transcriptional Deficits and Embryonic Lethality That Can Be Rescued by Human IKBKAP

Chen

Hims

Shetty

et al. 2009

Molecular and Cellular Biology

Self Cite

107

119

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“…Both YACs also carry the genetic marker D9S299, indicating a more precise localization of hCTL1 to 9q31.2. D9S299 is just proximal to the locus of mutation for familial dysautonomia (MIM 223900) (20).…”

Section: Sequence Analysis and Alignment Of The Members Of The Ctl Famentioning

confidence: 99%

An electric lobe suppressor for a yeast choline transport mutation belongs to a new family of transporter-like proteins

O’Regan

Traiffort

Ruat

et al. 2000

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

115

149

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Choline is an important metabolite in all cells due to the major contribution of phosphatidylcholine to the production of membranes, but it takes on an added role in cholinergic neurons where it participates in the synthesis of the neurotransmitter acetylcholine. We have cloned a suppressor for a yeast choline transport mutation from a Torpedo electric lobe yeast expression library by functional complementation. The full-length clone encodes a protein with 10 putative transmembrane domains, two of which contain transporter-like motifs, and whose expression increased high-affinity choline uptake in mutant yeast. The gene was called CTL1 for its choline transporter-like properties. The homologous rat gene, rCTL1, was isolated and found to be highly expressed as a 3.5-kb transcript in the spinal cord and brain and as a 5-kb transcript in the colon. In situ hybridization showed strong expression of rCTL1 in motor neurons and oligodendrocytes and to a lesser extent in various neuronal populations throughout the rat brain. High levels of rCTL1 were also identified in the mucosal cell layer of the colon. Although the sequence of the CTL1 gene shows clear homology with a single gene in Caenorhabditis elegans, several homologous genes are found in mammals (CTL2-4). These results establish a new family of genes for transporter-like proteins in eukaryotes and suggest that one of its members, CTL1, is involved in supplying choline to certain cell types, including a specific subset of cholinergic neurons. C ells contain large amounts of choline incorporated in their membranes, and all plant and animal cells, including unicellular organisms, absorb free choline as a nutrient. At cholinergic nerve terminals, the sodium-dependent high affinity choline uptake mechanism that is coupled to acetylcholine synthesis has been particularly well characterized at the functional level (1-3) but has thus far eluded diverse attempts at identification based on protein purification (4), even in conjunction with the use of a selective and irreversible ligand (5).The yeast choline transporter has been isolated by homologous complementation by using a choline transport deficient yeast strain (6), and heterologous complementation of yeast mutants with a yeast expression library made with Arabidopsis thaliana cDNA has been used to identify the potassium transporter of plants (7). We decided to adapt the strategy of complementation cloning to the problem of neuronal choline transport by using choline transport deficient yeast with the highly cholinergic electric lobes of Torpedo as a source of cDNA. However, the single clone isolated, capable of partially restoring choline uptake in the mutant yeast, did not resemble the yeast choline transporter (8) and is thus considered to be a heterologous suppressor for the choline transport mutation. We report the sequences of genes both homologous and orthologous to the Torpedo choline transporter-like protein, tCTL1, and we begin the characterization of this new family of transmembrane proteins by studying ...

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“…The latter loss may ultimately lead to blindness (4,5). More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3,6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3,6).…”

mentioning

confidence: 99%

“…More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3,6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3,6). The protein encoded by the IKBKAP/ELP1 gene, IKAP/ELP1, is a scaffolding protein for the six-subunit Elongator complex (ELP1-ELP6), which modifies tRNAs during translation (7).…”

mentioning

confidence: 99%

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

Ohlen

Russell

Brownstein

et al. 2017

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

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Hereditary sensory and autonomic neuropathy type III, or familial dysautonomia [FD; Online Mendelian Inheritance in Man (OMIM) 223900], affects the development and long-term viability of neurons in the peripheral nervous system (PNS) and retina. FD is caused by a point mutation in the gene IKBKAP/ELP1 that results in a tissue-specific reduction of the IKAP/ELP1 protein, a subunit of the Elongator complex. Hallmarks of the disease include vasomotor and cardiovascular instability and diminished pain and temperature sensation caused by reductions in sensory and autonomic neurons. It has been suggested but not demonstrated that mitochondrial function may be abnormal in FD. We previously generated an Ikbkap/Elp1 conditional-knockout mouse model that recapitulates the selective death of sensory (dorsal root ganglia) and autonomic neurons observed in FD. We now show that in these mice neuronal mitochondria have abnormal membrane potentials, produce elevated levels of reactive oxygen species, are fragmented, and do not aggregate normally at axonal branch points. The small hydroxylamine compound BGP-15 improved mitochondrial function, protecting neurons from dying in vitro and in vivo, and promoted cardiac innervation in vivo. Given that impairment of mitochondrial function is a common pathological component of neurodegenerative diseases such as amyotrophic lateral sclerosis and Alzheimer's, Parkinson's, and Huntington's diseases, our findings identify a therapeutic approach that may have efficacy in multiple degenerative conditions.T he autonomic nervous system is essential for homeostasis, and its disruption in familial dysautonomia (FD) can have fatal consequences resulting from cardiovascular instability, respiratory dysfunction, and/or sudden death during sleep (1-3). In addition to developmental decreases in the number of sensory and autonomic neurons, FD patients undergo a progressive loss of peripheral neurons and retinal ganglion cells. The latter loss may ultimately lead to blindness (4, 5). More than 98% of FD cases result from a single base substitution (IVS20+6T > C) in the IKBKAP/ELP1 gene (3, 6). This mutation is carried by 1 in 27 to 1 in 32 Ashkenazi Jews (3, 6). The protein encoded by the IKBKAP/ELP1 gene, IKAP/ELP1, is a scaffolding protein for the six-subunit Elongator complex (ELP1-ELP6), which modifies tRNAs during translation (7). Why reduction in the IKAP/ ELP1 protein results in neuronal death is unknown, and we have sought to elucidate the cellular and molecular mechanisms that cause progressive neurodegeneration in FD to help identify treatments that improve neuronal function and viability.Accumulating evidence indicates that cells from FD patients and from mouse models with deletions in the Elongator subunits Ikbkap/Elp1 or Elp3 experience intracellular stress (4,5,(8)(9)(10) resulting from the direct and/or indirect consequences of impaired translation (7, 11). The C terminus of IKAP/ELP1 has been shown to bind c-Jun N-terminal kinase (JNK) and to regulate JNK cytosolic stress signaling (12)....

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Precise Genetic Mapping and Haplotype Analysis of the Familial Dysautonomia Gene on Human Chromosome 9q31

Cited by 66 publications

References 36 publications

Loss of Mouse Ikbkap, a Subunit of Elongator, Leads to Transcriptional Deficits and Embryonic Lethality That Can Be Rescued by Human IKBKAP

Loss of Mouse Ikbkap, a Subunit of Elongator, Leads to Transcriptional Deficits and Embryonic Lethality That Can Be Rescued by Human IKBKAP

An electric lobe suppressor for a yeast choline transport mutation belongs to a new family of transporter-like proteins

BGP-15 prevents the death of neurons in a mouse model of familial dysautonomia

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