Significantly Elevated <i>FMR1</i> mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing

Significantly Elevated <i>FMR1</i> mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing

Although fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with &#8805;200 cytosine-guanine-guanine (CGG) repeats, and a decrease in <i>FMR1</i> mRNA and its protein (FMRP), incomplete silencing has been associated with more severe autism features i...

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Main Authors: Michael Field, Tracy Dudding-Byth, Marta Arpone, Emma K. Baker, Solange M. Aliaga, Carolyn Rogers, Chriselle Hickerton, David Francis, Dean G. Phelan, Elizabeth E. Palmer, David J. Amor, Howard Slater, Lesley Bretherton, Ling Ling, David E. Godler
Format: Article
Language:English
Published: MDPI AG 2019-08-01
Series:International Journal of Molecular Sciences
Subjects:
fragile X syndrome
autism
RNA toxicity
DNA methylation
mosaicism
pediatrics
MS-QMA
AmplideX
Online Access:https://www.mdpi.com/1422-0067/20/16/3907
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spelling doaj-62efb1f2e5e6435a990c53fdfece87ff2020-11-25T02:35:12ZengMDPI AGInternational Journal of Molecular Sciences1422-00672019-08-012016390710.3390/ijms20163907ijms20163907Significantly Elevated <i>FMR1</i> mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X TestingMichael Field0Tracy Dudding-Byth1Marta Arpone2Emma K. Baker3Solange M. Aliaga4Carolyn Rogers5Chriselle Hickerton6David Francis7Dean G. Phelan8Elizabeth E. Palmer9David J. Amor10Howard Slater11Lesley Bretherton12Ling Ling13David E. Godler14Genetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, AustraliaGenetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, AustraliaDiagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, AustraliaDiagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, AustraliaDiagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, AustraliaGenetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, AustraliaDiagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, AustraliaVictorian Clinical Genetics Services, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, AustraliaVictorian Clinical Genetics Services, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, AustraliaGenetics of Learning Disability Service, Hunter Genetics, Waratah, NSW 2298, AustraliaDiagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, AustraliaDiagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, AustraliaDiagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, AustraliaDiagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, AustraliaDiagnosis and Development, Murdoch Children’s Research Institute, Royal Children’s Hospital, Parkville, VIC 3052, AustraliaAlthough fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with &#8805;200 cytosine-guanine-guanine (CGG) repeats, and a decrease in <i>FMR1</i> mRNA and its protein (FMRP), incomplete silencing has been associated with more severe autism features in FXS males. This study reports on brothers (B1 and B2), aged 5 and 2 years, with autistic features and language delay, but a higher non-verbal IQ in comparison to typical FXS. CGG sizing using AmplideX PCR only identified premutation (PM: 55&#8722;199 CGGs) alleles in blood. Similarly, follow-up in B1 only revealed PM alleles in saliva and skin fibroblasts; whereas, an FM expansion was detected in both saliva and buccal DNA of B2. While Southern blot analysis of blood detected an unmethylated FM, methylation analysis with a more sensitive methodology showed that B1 had partially methylated PM alleles in blood and fibroblasts, which were completely unmethylated in buccal and saliva cells. In contrast, B2 was partially methylated in all tested tissues. Moreover, both brothers had <i>FMR1</i> mRNA ~5 fold higher values than those of controls, FXS and PM cohorts. In conclusion, the presence of unmethylated FM and/or PM in both brothers may lead to an overexpression of toxic expanded mRNA in some cells, which may contribute to neurodevelopmental problems, including elevated autism features.https://www.mdpi.com/1422-0067/20/16/3907fragile X syndromeautismRNA toxicityDNA methylationmosaicismpediatricsMS-QMAAmplideX
collection DOAJ
language English
format Article
sources DOAJ
author Michael Field
Tracy Dudding-Byth
Marta Arpone
Emma K. Baker
Solange M. Aliaga
Carolyn Rogers
Chriselle Hickerton
David Francis
Dean G. Phelan
Elizabeth E. Palmer
David J. Amor
Howard Slater
Lesley Bretherton
Ling Ling
David E. Godler
spellingShingle Michael Field
Tracy Dudding-Byth
Marta Arpone
Emma K. Baker
Solange M. Aliaga
Carolyn Rogers
Chriselle Hickerton
David Francis
Dean G. Phelan
Elizabeth E. Palmer
David J. Amor
Howard Slater
Lesley Bretherton
Ling Ling
David E. Godler
Significantly Elevated <i>FMR1</i> mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing
International Journal of Molecular Sciences
fragile X syndrome
autism
RNA toxicity
DNA methylation
mosaicism
pediatrics
MS-QMA
AmplideX
author_facet Michael Field
Tracy Dudding-Byth
Marta Arpone
Emma K. Baker
Solange M. Aliaga
Carolyn Rogers
Chriselle Hickerton
David Francis
Dean G. Phelan
Elizabeth E. Palmer
David J. Amor
Howard Slater
Lesley Bretherton
Ling Ling
David E. Godler
author_sort Michael Field
title Significantly Elevated <i>FMR1</i> mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing
title_short Significantly Elevated <i>FMR1</i> mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing
title_full Significantly Elevated <i>FMR1</i> mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing
title_fullStr Significantly Elevated <i>FMR1</i> mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing
title_full_unstemmed Significantly Elevated <i>FMR1</i> mRNA and Mosaicism for Methylated Premutation and Full Mutation Alleles in Two Brothers with Autism Features Referred for Fragile X Testing
title_sort significantly elevated <i>fmr1</i> mrna and mosaicism for methylated premutation and full mutation alleles in two brothers with autism features referred for fragile x testing
publisher MDPI AG
series International Journal of Molecular Sciences
issn 1422-0067
publishDate 2019-08-01
description Although fragile X syndrome (FXS) is caused by a hypermethylated full mutation (FM) expansion with &#8805;200 cytosine-guanine-guanine (CGG) repeats, and a decrease in <i>FMR1</i> mRNA and its protein (FMRP), incomplete silencing has been associated with more severe autism features in FXS males. This study reports on brothers (B1 and B2), aged 5 and 2 years, with autistic features and language delay, but a higher non-verbal IQ in comparison to typical FXS. CGG sizing using AmplideX PCR only identified premutation (PM: 55&#8722;199 CGGs) alleles in blood. Similarly, follow-up in B1 only revealed PM alleles in saliva and skin fibroblasts; whereas, an FM expansion was detected in both saliva and buccal DNA of B2. While Southern blot analysis of blood detected an unmethylated FM, methylation analysis with a more sensitive methodology showed that B1 had partially methylated PM alleles in blood and fibroblasts, which were completely unmethylated in buccal and saliva cells. In contrast, B2 was partially methylated in all tested tissues. Moreover, both brothers had <i>FMR1</i> mRNA ~5 fold higher values than those of controls, FXS and PM cohorts. In conclusion, the presence of unmethylated FM and/or PM in both brothers may lead to an overexpression of toxic expanded mRNA in some cells, which may contribute to neurodevelopmental problems, including elevated autism features.
topic fragile X syndrome
autism
RNA toxicity
DNA methylation
mosaicism
pediatrics
MS-QMA
AmplideX
url https://www.mdpi.com/1422-0067/20/16/3907
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