TY - JOUR
T1 - Allelic Expression Imbalance Promoting a Mutant PEX6 Allele Causes Zellweger Spectrum Disorder
AU - Falkenberg, Kim D.
AU - Braverman, Nancy E.
AU - Moser, Ann B.
AU - Steinberg, Steven J.
AU - Klouwer, Femke C.C.
AU - Schlüter, Agatha
AU - Ruiz, Montserrat
AU - Pujol, Aurora
AU - Engvall, Martin
AU - Naess, Karin
AU - van Spronsen, Franc Jan
AU - Körver-Keularts, Irene
AU - Rubio-Gozalbo, M. Estela
AU - Ferdinandusse, Sacha
AU - Wanders, Ronald J.A.
AU - Waterham, Hans R.
N1 - Funding Information:
Work at the Laboratory Genetic Metabolic Diseases in Amsterdam was supported by Marie Curie Initial Training Networks action ( FP7-2012-PERFUME-316723 to K.D.F. and H.R.W.), at Kennedy Krieger Institute by the grant “ Intellectual and Developmental Disabilities Research Centers 2013” Type: (1 U54 HD079123-01A1) NICHD , and at the Neurometabolic Diseases Laboratory by grants from the Autonomous Government of Catalonia ( SGR 2014SGR1430 ), the Spanish Center for Biomedical Research on Rare Diseases (CIBERER, ER15PR02ACCI14 ), the Foundation Marató de TV3 ( 2014-0830 ), and the Hesperia Foundation .
Publisher Copyright:
© 2017 American Society of Human Genetics
PY - 2017/12/7
Y1 - 2017/12/7
N2 - Zellweger spectrum disorders (ZSDs) are autosomal-recessive disorders that are caused by defects in peroxisome biogenesis due to bi-allelic mutations in any of 13 different PEX genes. Here, we identified seven unrelated individuals affected with an apparent dominant ZSD in whom a heterozygous mutant PEX6 allele (c.2578C>T [p.Arg860Trp]) was overrepresented due to allelic expression imbalance (AEI). We demonstrated that AEI of PEX6 is a common phenomenon and is correlated with heterozygosity for a frequent variant in the 3′ untranslated region (UTR) of the mutant allele, which disrupts the most distal of two polyadenylation sites. Asymptomatic parents, who were heterozygous for PEX c.2578C>T, did not show AEI and were homozygous for the 3′ UTR variant. Overexpression models confirmed that the overrepresentation of the pathogenic PEX6 c.2578T variant compared to wild-type PEX6 c.2578C results in a peroxisome biogenesis defect and thus constitutes the cause of disease in the affected individuals. AEI promoting the overrepresentation of a mutant allele might also play a role in other autosomal-recessive disorders, in which only one heterozygous pathogenic variant is identified.
AB - Zellweger spectrum disorders (ZSDs) are autosomal-recessive disorders that are caused by defects in peroxisome biogenesis due to bi-allelic mutations in any of 13 different PEX genes. Here, we identified seven unrelated individuals affected with an apparent dominant ZSD in whom a heterozygous mutant PEX6 allele (c.2578C>T [p.Arg860Trp]) was overrepresented due to allelic expression imbalance (AEI). We demonstrated that AEI of PEX6 is a common phenomenon and is correlated with heterozygosity for a frequent variant in the 3′ untranslated region (UTR) of the mutant allele, which disrupts the most distal of two polyadenylation sites. Asymptomatic parents, who were heterozygous for PEX c.2578C>T, did not show AEI and were homozygous for the 3′ UTR variant. Overexpression models confirmed that the overrepresentation of the pathogenic PEX6 c.2578T variant compared to wild-type PEX6 c.2578C results in a peroxisome biogenesis defect and thus constitutes the cause of disease in the affected individuals. AEI promoting the overrepresentation of a mutant allele might also play a role in other autosomal-recessive disorders, in which only one heterozygous pathogenic variant is identified.
KW - PEX1
KW - PEX6
KW - dominant-negative
KW - metabolic
KW - peroxisomal disorder
KW - peroxisome
KW - peroxisome biogenesis disorder
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U2 - 10.1016/j.ajhg.2017.11.007
DO - 10.1016/j.ajhg.2017.11.007
M3 - Article
C2 - 29220678
AN - SCOPUS:85037370535
SN - 0002-9297
VL - 101
SP - 965
EP - 976
JO - American journal of human genetics
JF - American journal of human genetics
IS - 6
ER -