CHD7, the gene mutated in CHARGE syndrome, regulates genes involved in neural crest cell guidance.

[kallmann syndrome]

Heterozygous loss of function mutations in CHD 7 (chromodomain helicase DNA-binding protein 7 ) lead to CHARGE syndrome , a complex developmental disorder affecting craniofacial structures , cranial nerves and several organ systems . Recently , it was demonstrated that CHD 7 is essential for the formation of multipotent migratory neural crest cells , which migrate from the neural tube to many regions of the embryo , where they differentiate into various tissues including craniofacial and heart structures . So far , only few CHD 7 target genes involved in neural crest cell development have been identified and the role of CHD 7 in neural crest cell guidance and the regulation of mesenchymal-epithelial transition are unknown . Therefore , we undertook a genome-wide microarray expression analysis on wild-type and CHD 7 deficient (Chd 7 (Whi /+) and Chd 7 (Whi /Whi )) mouse embryos at day 9 .5 , a time point of neural crest cell migration . We identified 98 differentially expressed genes between wild-type and Chd 7 (Whi /Whi ) embryos . Interestingly , many misregulated genes are involved in neural crest cell and axon guidance such as semaphorins and ephrin receptors . By performing knockdown experiments for Chd 7 in Xenopus laevis embryos , we found abnormalities in the expression pattern of Sema 3 a , a protein involved in the pathogenesis of Kallmann syndrome , in vivo . In addition , we detected non-synonymous SEMA 3 A variations in 3 out of 45 CHD 7 -negative CHARGE patients . In summary , we discovered for the first time that Chd 7 regulates genes involved in neural crest cell guidance , demonstrating a new aspect in the pathogenesis of CHARGE syndrome . Furthermore , we showed for Sema 3 a a conserved regulatory mechanism across different species , highlighting its significance during development . Although we postulated that the non-synonymous SEMA 3 A variants which we found in CHD 7 -negative CHARGE patients alone are not sufficient to produce the phenotype , we suggest an important modifier role for SEMA 3 A in the pathogenesis of this multiple malformation syndrome .

Diseases
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Diseases presenting "first time" symptom

achondroplasia

acute rheumatic fever

adrenal incidentaloma

adrenomyeloneuropathy

alpha-thalassemia

aniridia

aromatase deficiency

canavan disease

carcinoma of the gallbladder

cholangiocarcinoma

classical phenylketonuria

congenital adrenal hyperplasia

congenital toxoplasmosis

cowden syndrome

cushing syndrome

cutaneous mastocytosis

dedifferentiated liposarcoma

dentin dysplasia

dentinogenesis imperfecta

dracunculiasis

dystrophic epidermolysis bullosa

epidermolysis bullosa simplex

erdheim-chester disease

erythropoietic protoporphyria

esophageal adenocarcinoma

esophageal carcinoma

esophageal squamous cell carcinoma

fabry disease

familial mediterranean fever

gm1 gangliosidosis

harlequin ichthyosis

heparin-induced thrombocytopenia

hirschsprung disease

hodgkin lymphoma, classical

holt-oram syndrome

hydrocephalus with stenosis of the aqueduct of sylvius

junctional epidermolysis bullosa

kabuki syndrome

kallmann syndrome

liposarcoma

locked-in syndrome

lymphangioleiomyomatosis

malignant atrophic papulosis

megacystis-microcolon-intestinal hypoperistalsis syndrome

monosomy 21

neuralgic amyotrophy

oculocutaneous albinism

oligodontia

omenn syndrome

oral submucous fibrosis

papillon-lefèvre syndrome

pendred syndrome

phenylketonuria

primary effusion lymphoma

primary hyperoxaluria type 1

severe combined immunodeficiency

sneddon syndrome

triple a syndrome

trochlear dysplasia

von hippel-lindau disease

waldenström macroglobulinemia

well-differentiated liposarcoma

werner syndrome

wiskott-aldrich syndrome

wolf-hirschhorn syndrome

x-linked adrenoleukodystrophy

zellweger syndrome

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