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What I Know Best: Holoprosencephaly Max Muenke Medical Genetics Branch National Human Genome Research Institute National Institutes of Health B th d M Bethesda, Maryland, l d USA [email protected] Second European Course in Clinical Dysmorphology Rome, March 28-29, 2008 Clinical Projects j • Holoprosencephaly QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. • ADHD QuickTime™ and a TIFF (LZW) decompressor are needed to see this picture. • “Muenke” “M k ” syndrome d Holoprosencephaly (HPE) Nodal and Hedgehog Signaling Low L Cholesterol NODAL SHH CDO TDGF1 DISP1 PTC TGIF FOXH1 SIX3 ZIC2 GLI2 Sonic Hedgehog, Hedgehog Cholesterol, Brain Development, and Prematurity H l Holoprosencephaly h l (HPE) • Midline Defect of the Developing Forebrain and Face • Prevalence: 1 in 250 Early Embryos 1 in 10,000 , LiveLive-born Infants less than 1:100,000 over 1 Y/O • Etiology: Extremely Heterogeneous Alobar HPE Semilobar HPE Holoprosencephaly p p y “The Face Predicts the Brain” Holoprosencephaly Gene Carriers Causes of HPE • Cytogenetic Anomalies • Gene Mutations • Defects of Cholesterol Biosynthesis • Gene/Environment G /E i t Interactions I t ti Causes of HPE • Cytogenetic Anomalies • Gene Mutations • Defects of Cholesterol Biosynthesis • Gene/Environment G /E i t Interactions I t ti Low maternal cholesterol? Maternal diabetes? Alcohol exposure? p Retinoic acid exposure? Cytogenetic Anomalies in HPE Positional Cloning of HPE Genes HNF3β? β TGIF ZIC2 SHH SIX3 DISPATCHED Microdeletion Detection by Multicolor FISH Dispatched p : 1q41 q SIX3 : 2p21 SHH : 7q36 ZIC2 : 13q32 TGIF : 18p11 HNF3 β : 20p11 p Microdeletion of TGIF 18 2 1 18 7 13 13 20 7 1 20 2 46,XY.ish del(18)(p11.3p11.3)(TGIF del(18)(p11.3p11.3)(TGIF--) Microdeletion Detection • Multicolor FISH • qPCR • MLPA • aCGH Familial Holoprosencephaly p p y Positional Cloning of HPE Genes SHH Sonic Hedgehog Cleavage and Modification Palmitate Cholesterol Sonic Hedgehog Cleavage C25S and Modification C198X generates Shh-N without cholesterol or C-terminus Palmitate Cholesterol Sonic Hedgehog Cleavage and Modification Human Hedgehog Acyltransferase (HHAT) Palmitate Cholesterol SHH Signaling SHH Signaling Nodal and Hedgehog Signaling Low L Cholesterol NODAL SHH CDO TDGF1 DISP1 PTC TGIF FOXH1 SIX3 ZIC2 GLI2 Two Mutations in HPE Patients SHH Mutations in Families with SCI Cholesterol biosynthesis and holoprosencephaly Background: Pertubations of cholesterol homeostasis are an important factor in HPE pathogenesis in animal models Purpose: p Are alterations in cholesterol biosynthesis are associated with HPE in humans? Methods: In vitro loading test using 14C-acetate C acetate as a substrate which identifies C27 sterols in lymphoblasts and comparison with GCMS Cholesterol biosynthesis and holoprosencephaly Results: 22 of 230 patients (9.6%) with various HPE phenotypes had abnormal sterol profiles that were different from known defects Conclusion: Impaired cholesterol biosynthesis contributes to the etiology of HPE in humans Future F t studies: t di A l i off enzyme defects Analysis d f t that th t lead to the abnormal sterol patterns in HPE patients Summary: Causes of HPE • Cytogenetic Anomalies:~50 Anomalies:~50--60% • Gene Mutations: ~10 ~10--15% • Defects of Cholesterol Biosynthesis: ~ 5% • Gene/Environment Interactions: ~30--40% (?) ~30 Holoprosencephaly “Does Does the Face Predict the Cause?” Cause? With few exceptions: NO Facial findings in children with HPE and ZIC2 mutations Facial findings in children with ith pituitary it it anomalies and GLI2 mutations Brain Development and Cholesterol Maternal cholesterol in early embryogenesis is crucial for normal craniofacial and brain development. development Modified d from C.C. Hu ui Statins Cholesterol Biosynthesis First Trimester Statins CNS A Anomalies li HPE,, NTD Limb Reduction Defects VACTERL Brain Development and Cholesterol •Pilot study of cholesterol in the parents and children with isolated HPE Result: significantly lower cholesterol h l t l in i mothers th Brain Development and Cholesterol •HPE in patients with Smith Smith-LemliLemli Opitz Syndrome (SLOS) Acknowledgements g Holoprosencephaly p p y Cholesterol Clinicians around the world Robin Edison, NIH Kate Berg, NIH Alan Remaley, Remaley NIH Erich Roessler Roessler, NIH Kenia El-Jaick, NIH, now UFRJ J.P. Karkera, NIH Claude Bendavid, NIH, U. Rennes Maia Ouspenskaia, NIH Roger Stevenson, Greenwood Genetics Ctr Jean Golding, U. Bristol, UK Richard Kelley, KKI/JHU Ben Feldman, Feldman NIH Jeff Ming, CHOP/Penn, now Merck Bassem Haddad, Georgetown U.
