Somatic mutations in GLI3 and OFD1 involved in sonic hedgehog signaling cause hypothalamic hamartoma

Posted on Posted in AMRC Research

Date: 25 Mar 2016


Hypothalamic hamartoma (HH) is a congenital anomalous brain tumor associated with drug-resistant epilepsy, gelastic seizures, cognitive deficits, behavioral abnormalities, and precocious puberty.[1, 2] HH has intrinsic epileptogenesis;[3, 4] thus, elucidating the pathological basis of HH development would facilitate understanding for its epileptogenesis. Although most HHs are diagnosed without any other systemic features, HH is often observed as one of the clinical features of different dysmorphic syndromes including Pallister–Hall syndrome (PHS) and oral-facial-digital syndrome (OFD) types I and VI; syndromes that have overlapping phenotypes such as HH and polydactyly.[5-7] Truncation mutations in GLI3, a transcription factor that modulates Shh signaling are known to cause PHS.[5, 8-10] Full-length GLI3 functions as a transcriptional activator in the presence of Shh, and is cleaved to form a repressor in the absence of Shh.[11] GLI3 mutations in PHS patients are accumulated in the middle third of the gene,[5, 8, 10] suggesting that mutant GLI3 would function as a constitutive repressor. Severe truncation mutations in OFD1 are found in OFD type I, which is an X-linked dominant disorder with male lethality.[12, 13] OFD1 encodes a centrosomal/basal body protein that localizes to the base of primary cilia.[14-16] The primary cilium is required for Shh signaling,[17] and Ofd1-deficient male mice showed reduced expression of the Shh target genes Ptch1 and Gli1.[18] Therefore, HH is found in two disorders that have GLI3 and OFD1 mutations, both of which appear to reduce Shh signaling. Autosomal recessive mutations in C5orf42, an uncharacterized protein consisting of 3,198-amino acids, have been reported to cause OFD type VI.[19]


Somatic mutation has recently been shown to be one of the underlying causes for the phenotypic variation in genetic diseases.[20, 21] For example, germline and somatic mutations in genes involved in PI3K-AKT3-mTOR pathway cause a spectrum of megalencephaly related disorders.[22, 23] In HH, somatic chromosomal abnormalities involving the GLI3 locus and a somatic GLI3 mutation have been reported,[24, 25] suggesting that somatic mutations are important factors in HH. In this study, we found hamartoma-specific truncation mutations in GLI3 and OFD1 in two and three individuals, respectively, suggesting that impaired Shh signaling by germline and somatic mutations can cause a spectrum of human disorders related to HH.


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Department of Human Genetics,
Yokohama City University Graduate School of Medicine

Fukuura 3-9, Kanazawa-ku, Yokohama, Japan 236-0004