TY - JOUR
T1 - Sema3a plays a role in the pathogenesis of CHARGE syndrome
AU - Ufartes, Roser
AU - Schwenty-Lara, Janina
AU - Freese, Luisa
AU - Neuhofer, Christiane
AU - Möller, Janika
AU - Wehner, Peter
AU - van Ravenswaaij-Arts, Conny M A
AU - Wong, Monica T Y
AU - Schanze, Ina
AU - Tzschach, Andreas
AU - Bartsch, Oliver
AU - Borchers, Annette
AU - Pauli, Silke
N1 - © The Author 2018. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.
PY - 2018/4/15
Y1 - 2018/4/15
N2 - CHARGE syndrome is an autosomal dominant malformation disorder caused by heterozygous loss of function mutations in the chromatin remodeler CHD7. Chd7 regulates the expression of Sema3a, which also contributes to the pathogenesis of Kallmann syndrome, a heterogeneous condition with the typical features hypogonadotropic hypogonadism and an impaired sense of smell. Both features are common in CHARGE syndrome suggesting that SEMA3A may provide a genetic link between these syndromes. Indeed, we find evidence that SEMA3A plays a role in the pathogenesis of CHARGE syndrome. First, Chd7 is enriched at the Sema3a promotor in neural crest cells and loss of function of Chd7 inhibits Sema3a expression. Second, using a Xenopus CHARGE model, we show that human SEMA3A rescues Chd7 loss of function. Third, to elucidate if SEMA3A mutations in addition to CHD7 mutations also contribute to the severity of the CHARGE phenotype, we screened 31 CHD7-positive patients and identified one patient with a heterozygous non-synonymous SEMA3A variant, c. 2002A> G (p. I668V). By analyzing protein expression and processing, we did not observe any differences of the p. I668V variant compared with wild-type SEMA3A, while a pathogenic SEMA3A variant p. R66W recently described in a patient with Kallmann syndrome did affect protein secretion. Furthermore, the p. I668V variant, but not the pathogenic p. R66W variant, rescues Chd7 loss of function in Xenopus, indicating that the p. I668V variant is likely benign. Thus, SEMA3A is part of an epigenetic loop that plays a role in the pathogenesis of CHARGE syndrome, however, it seems not to act as a common direct modifier.
AB - CHARGE syndrome is an autosomal dominant malformation disorder caused by heterozygous loss of function mutations in the chromatin remodeler CHD7. Chd7 regulates the expression of Sema3a, which also contributes to the pathogenesis of Kallmann syndrome, a heterogeneous condition with the typical features hypogonadotropic hypogonadism and an impaired sense of smell. Both features are common in CHARGE syndrome suggesting that SEMA3A may provide a genetic link between these syndromes. Indeed, we find evidence that SEMA3A plays a role in the pathogenesis of CHARGE syndrome. First, Chd7 is enriched at the Sema3a promotor in neural crest cells and loss of function of Chd7 inhibits Sema3a expression. Second, using a Xenopus CHARGE model, we show that human SEMA3A rescues Chd7 loss of function. Third, to elucidate if SEMA3A mutations in addition to CHD7 mutations also contribute to the severity of the CHARGE phenotype, we screened 31 CHD7-positive patients and identified one patient with a heterozygous non-synonymous SEMA3A variant, c. 2002A> G (p. I668V). By analyzing protein expression and processing, we did not observe any differences of the p. I668V variant compared with wild-type SEMA3A, while a pathogenic SEMA3A variant p. R66W recently described in a patient with Kallmann syndrome did affect protein secretion. Furthermore, the p. I668V variant, but not the pathogenic p. R66W variant, rescues Chd7 loss of function in Xenopus, indicating that the p. I668V variant is likely benign. Thus, SEMA3A is part of an epigenetic loop that plays a role in the pathogenesis of CHARGE syndrome, however, it seems not to act as a common direct modifier.
KW - NEURAL CREST CELLS
KW - KALLMANN-SYNDROME
KW - HYPOGONADOTROPIC HYPOGONADISM
KW - PHENOTYPIC SPECTRUM
KW - XENOPUS-EMBRYOS
KW - AXON GUIDANCE
KW - SHORT STATURE
KW - CHD7
KW - MUTATIONS
KW - MIGRATION
U2 - 10.1093/hmg/ddy045
DO - 10.1093/hmg/ddy045
M3 - Article
C2 - 29432577
VL - 27
SP - 1343
EP - 1352
JO - Human Molecular Genetics
JF - Human Molecular Genetics
SN - 0964-6906
IS - 8
ER -