Decreased density of ganglia and neurons in the myenteric plexus of familial dysautonomia patients

Bar-Shai, Amir; Maayan, Channa; Vromen, Amos; Udassin, Raphael; Nissan, Aviram; Freund, Herbert R.; Hanani, Menachem

doi:10.1016/j.jns.2004.02.017

Cited by 19 publications

(13 citation statements)

References 35 publications

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“…Interestingly, the region encompassing our 6 IKBKAP associated SNPs includes the region where FD-causing mutations lie. Ikbkap is expressed in the rat developing gut and IKBKAP in the human colon, supporting a biological role for this gene in the development of enteric nervous system (Bar-Shai et al 2004; Mezey et al 2003). …”

Section: Resultsmentioning

confidence: 87%

Fine mapping of the 9q31 Hirschsprung’s disease locus

et al. 2010

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Hirschsprung’s disease (HSCR) is a congenital disorder characterised by the absence of ganglia along variable lengths of the intestine. The RET gene is the major HSCR gene. Reduced penetrance of RET mutations and phenotypic variability suggest the involvement of additional modifying genes in the disease. A RET-dependent modifier locus was mapped to 9q31 in families bearing no coding sequence (CDS) RET mutations. Yet, the 9q31 causative locus is to be identified. To fine-map the 9q31 region, we genotyped 301 tag-SNPs spanning 7 Mb on 137 HSCR Dutch trios. This revealed two HSCR-associated regions that were further investigated in 173 Chinese HSCR patients and 436 controls using the genotype data obtained from a genome-wide association study recently conducted. Within one of the two identified regions SVEP1 SNPs were found associated with Dutch HSCR patients in the absence of RET mutations. This ratifies the reported linkage to the 9q31 region in HSCR families with no RET CDS mutations. However, this finding could not be replicated. In Chinese, HSCR was found associated with IKBKAP. In contrast, this association was stronger in patients carrying RET CDS mutations with p = 5.10 × 10−6 [OR = 3.32 (1.99, 5.59)] after replication. The HSCR-association found for IKBKAP in Chinese suggests population specificity and implies that RET mutation carriers may have an additional risk. Our finding is supported by the role of IKBKAP in the development of the nervous system.Electronic supplementary materialThe online version of this article (doi:10.1007/s00439-010-0813-8) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 87%

Fine mapping of the 9q31 Hirschsprung’s disease locus

et al. 2010

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“…The pathologic substrate of symptoms would appear similar in our patients. In addition, myenteric neuronal loss has been reported to affect immune and secretory function of the gut, giving rise to gastrointestinal tract disease 34. In our…”

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confidence: 74%

Neuronal intranuclear hyaline inclusion disease showing motor-sensory and autonomic neuropathy

Sone¹,

Hishikawa²,

Koike³

et al. 2005

Neurology

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“…Antisense RNA reduction of Ikbkap/Elp1 led to a significant reduction in enteric neurons including complete agangliogenesis of the distal intestine in zebrafish embryos [39]. These findings are analogous to the human FD gastroenteropathy which most likely results from reduced numbers of enteric neurons [43]. While trunk neural crest migration in chick and mouse does not require Ikbkap [27–29], reduction of Elp3 in Xenopus impairs neural crest migration [44].…”

Section: Non-mammalian Models Of Familial Dysautonomiamentioning

confidence: 99%

Animal and cellular models of familial dysautonomia

et al. 2017

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Since Riley and Day first described the clinical phenotype of patients with familial dysautonomia (FD) over 60 years ago, the field has made considerable progress clinically, scientifically, and translationally in treating and understanding the etiology of FD. FD is classified as a hereditary sensory and autonomic neuropathy (HSAN Type III) and is both a developmental and a progressive neurodegenerative condition that results from an autosomal recessive mutation in the gene IKBKAP, also known as ELP1. FD primarily impacts the peripheral nervous system but also manifests in central nervous system disruption, especially in the retina and optic nerve. While the disease is rare, the rapid progress being made in elucidating the molecular and cellular mechanisms mediating the demise of neurons in FD should provide insight into degenerative pathways common to many neurological disorders. Interestingly, the protein encoded by IKBKAP/ELP1, IKAP or ELP1, is a key scaffolding subunit of the six-subunit Elongator complex, and variants in other Elongator genes are associated with amyotrophic lateral sclerosis (ALS), intellectual disability, and Rolandic Epilepsy. Here we review the recent model systems that are revealing the molecular and cellular pathophysiological mechanisms mediating FD. These powerful model systems can now be used to test targeted therapeutics for mitigating neuronal loss in FD and potentially other disorders.

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Decreased density of ganglia and neurons in the myenteric plexus of familial dysautonomia patients

Cited by 19 publications

References 35 publications

Fine mapping of the 9q31 Hirschsprung’s disease locus

Fine mapping of the 9q31 Hirschsprung’s disease locus

Neuronal intranuclear hyaline inclusion disease showing motor-sensory and autonomic neuropathy

Animal and cellular models of familial dysautonomia

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