PMID- 31639285 OWN - NLM STAT- MEDLINE DCOM- 20200817 LR - 20240330 IS - 1552-4833 (Electronic) IS - 1552-4825 (Print) IS - 1552-4825 (Linking) VI - 179 IP - 12 DP - 2019 Dec TI - Mutations in the sonic hedgehog pathway cause macrocephaly-associated conditions due to crosstalk to the PI3K/AKT/mTOR pathway. PG - 2517-2531 LID - 10.1002/ajmg.a.61368 [doi] AB - The hedgehog (Hh) pathway is highly conserved and required for embryonic patterning and determination. Mutations in the Hh pathway are observed in sporadic tumors as well as under syndromic conditions. Common to these syndromes are the findings of polydactyly/syndactyly and brain overgrowth. The latter is also a finding most commonly observed in the cases of mutations in the PI3K/AKT/mTOR pathway. We have identified novel Hh pathway mutations and structural copy number variations in individuals with somatic overgrowth, macrocephaly, dysmorphic facial features, and developmental delay, which phenotypically closely resemble patients with phosphatase and tensin homolog (PTEN) mutations. We hypothesized that brain overgrowth and phenotypic overlap with syndromic overgrowth syndromes in these cases may be due to crosstalk between the Hh and PI3K/AKT/mTOR pathways. To test this, we modeled disease-associated variants by generating PTCH1 and Suppressor of Fused (SUFU) heterozygote cell lines using the CRISPR/Cas9 system. These cells demonstrate activation of PI3K signaling and increased phosphorylation of its downstream target p4EBP1 as well as a distinct cellular phenotype. To further investigate the mechanism underlying this crosstalk, we treated human neural stem cells with sonic hedgehog (SHH) ligand and performed transcriptional analysis of components of the mTOR pathway. These studies identified decreased expression of a set of mTOR negative regulators, leading to its activation. We conclude that there is a significant crosstalk between the SHH and PI3K/AKT/mTOR. We propose that this crosstalk is responsible for why mutations in PTCH1 and SUFU lead to macrocephaly phenotypes similar to those observed in PTEN hamartoma and other overgrowth syndromes associated with mutations in PI3K/AKT/mTOR pathway genes. CI - (c) 2019 Wiley Periodicals, Inc. FAU - Klein, Steven D AU - Klein SD AD - Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. FAU - Nguyen, Dzung C AU - Nguyen DC AD - Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. FAU - Bhakta, Viraj AU - Bhakta V AD - Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. FAU - Wong, Derek AU - Wong D AD - Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. FAU - Chang, Vivian Y AU - Chang VY AD - Division of Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. AD - Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. FAU - Davidson, Tom B AU - Davidson TB AD - Division of Hematology-Oncology, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. AD - Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. FAU - Martinez-Agosto, Julian A AU - Martinez-Agosto JA AUID- ORCID: 0000-0001-6776-6949 AD - Department of Human Genetics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. AD - Division of Medical Genetics, Department of Pediatrics, David Geffen School of Medicine, University of California, Los Angeles, Los Angeles, California. LA - eng GR - U54 HD087101/HD/NICHD NIH HHS/United States GR - UL1 TR000124/TR/NCATS NIH HHS/United States GR - K08 HL138305/HL/NHLBI NIH HHS/United States GR - P50 HD055784/HD/NICHD NIH HHS/United States GR - P50 CA211015/CA/NCI NIH HHS/United States GR - WT_/Wellcome Trust/United Kingdom GR - 9172/AS/Autism Speaks/United States GR - T32 GM008042/GM/NIGMS NIH HHS/United States PT - Case Reports PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't DEP - 20191022 PL - United States TA - Am J Med Genet A JT - American journal of medical genetics. Part A JID - 101235741 RN - 0 (Hedgehog Proteins) RN - EC 2.7.11.1 (Proto-Oncogene Proteins c-akt) RN - EC 2.7.11.1 (TOR Serine-Threonine Kinases) SB - IM MH - CRISPR-Cas Systems MH - Cell Line MH - Child, Preschool MH - Female MH - Gene Deletion MH - Haploinsufficiency MH - Hedgehog Proteins/*metabolism MH - Humans MH - Infant MH - Male MH - Megalencephaly/diagnosis/*genetics/*metabolism MH - Models, Biological MH - *Mutation MH - Neural Stem Cells MH - Phosphatidylinositol 3-Kinases/*metabolism MH - Proto-Oncogene Proteins c-akt/*metabolism MH - *Signal Transduction MH - TOR Serine-Threonine Kinases/*metabolism PMC - PMC7346528 MID - NIHMS1596987 COIS- CONFLICT OF INTEREST The authors have no potential conflict of interest. EDAT- 2019/10/23 06:00 MHDA- 2020/08/18 06:00 PMCR- 2020/07/09 CRDT- 2019/10/23 06:00 PHST- 2019/02/09 00:00 [received] PHST- 2019/06/12 00:00 [revised] PHST- 2019/09/09 00:00 [accepted] PHST- 2019/10/23 06:00 [pubmed] PHST- 2020/08/18 06:00 [medline] PHST- 2019/10/23 06:00 [entrez] PHST- 2020/07/09 00:00 [pmc-release] AID - 10.1002/ajmg.a.61368 [doi] PST - ppublish SO - Am J Med Genet A. 2019 Dec;179(12):2517-2531. doi: 10.1002/ajmg.a.61368. Epub 2019 Oct 22.