10q23.31 microduplication encompassing PTEN decreases mTOR signalling activity and is associated with autosomal dominant primary microcephaly

Danyllo Oliveira, Gabriela Ferraz Leal, Andréa L. Sertié, Luiz Carlos Caires, Ernesto Goulart, Camila Manso Musso, João Ricardo Mendes De Oliveira, Ana C.V. Krepischi, Angela Maria Vianna-Morgante, Mayana Zatz

Research output: Contribution to journalArticle

Abstract

Background: Hereditary primary microcephaly (MCPH) is mainly characterised by decreased occipitofrontal circumference and variable degree of intellectual disability. MCPH with a dominant pattern of inheritance is a rare condition, so far causally linked to pathogenic variants in the ALFY, DPP6, KIF11 and DYRK1A genes. Objective: This study aimed at identifying the causative variant of the autosomal dominant form of MCPH in a Brazilian family with three affected members. Methods: Following clinical evaluation of two sibs and their mother presenting with autosomal dominant MCPH, array comparative genome hybridisation was performed using genomic DNA from peripheral blood of the family members. Gene and protein expression studies were carried out in cultured skin fibroblasts. Results: A 382 kb microduplication at 10q23.31 was detected, encompassing the entire PTEN, KLLN and ATAD1 genes. PTEN haploinsufficiency has been causally associated with macrocephaly and autism spectrum disorder and, therefore, was considered the most likely candidate gene to be involved in this autosomal dominant form of MCPH. In the patients' fibroblasts, PTEN mRNA and protein were found to be overexpressed, and the phosphorylation patterns of upstream and downstream components of the mammalian target of rapamycin (mTOR) signalling pathway were dysregulated. Conclusions: Taken together, our results demonstrate that the identified submicroscopic 10q23.31 duplication in a family with MCPH leads to markedly increased expression of PTEN and reduced activity of the mTOR signalling pathway. These results suggest that the most probable pathomechanism underlying the microcephaly phenotype in this family involves downregulation of the mTOR pathway through overexpression of PTEN.

Original languageEnglish (US)
Pages (from-to)543-547
Number of pages5
JournalJournal of medical genetics
Volume56
Issue number8
DOIs
StatePublished - Aug 1 2019

Fingerprint

Sirolimus
Microcephaly
Fibroblasts
PTEN Phosphohydrolase
Megalencephaly
Genes
Haploinsufficiency
Inheritance Patterns
Comparative Genomic Hybridization
Intellectual Disability
Down-Regulation
Phosphorylation
Mothers
Phenotype
Gene Expression
Messenger RNA
Skin
Microcephaly autosomal dominant
DNA
Proteins

Keywords

  • copy number variation
  • molecular genetics
  • neurodevelopmental disorders
  • primary microcephaly

ASJC Scopus subject areas

  • Genetics
  • Genetics(clinical)

Cite this

10q23.31 microduplication encompassing PTEN decreases mTOR signalling activity and is associated with autosomal dominant primary microcephaly. / Oliveira, Danyllo; Leal, Gabriela Ferraz; Sertié, Andréa L.; Caires, Luiz Carlos; Goulart, Ernesto; Musso, Camila Manso; De Oliveira, João Ricardo Mendes; Krepischi, Ana C.V.; Vianna-Morgante, Angela Maria; Zatz, Mayana.

In: Journal of medical genetics, Vol. 56, No. 8, 01.08.2019, p. 543-547.

Research output: Contribution to journalArticle

Oliveira, D, Leal, GF, Sertié, AL, Caires, LC, Goulart, E, Musso, CM, De Oliveira, JRM, Krepischi, ACV, Vianna-Morgante, AM & Zatz, M 2019, '10q23.31 microduplication encompassing PTEN decreases mTOR signalling activity and is associated with autosomal dominant primary microcephaly', Journal of medical genetics, vol. 56, no. 8, pp. 543-547. https://doi.org/10.1136/jmedgenet-2018-105471
Oliveira, Danyllo ; Leal, Gabriela Ferraz ; Sertié, Andréa L. ; Caires, Luiz Carlos ; Goulart, Ernesto ; Musso, Camila Manso ; De Oliveira, João Ricardo Mendes ; Krepischi, Ana C.V. ; Vianna-Morgante, Angela Maria ; Zatz, Mayana. / 10q23.31 microduplication encompassing PTEN decreases mTOR signalling activity and is associated with autosomal dominant primary microcephaly. In: Journal of medical genetics. 2019 ; Vol. 56, No. 8. pp. 543-547.
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T1 - 10q23.31 microduplication encompassing PTEN decreases mTOR signalling activity and is associated with autosomal dominant primary microcephaly

AU - Oliveira, Danyllo

AU - Leal, Gabriela Ferraz

AU - Sertié, Andréa L.

AU - Caires, Luiz Carlos

AU - Goulart, Ernesto

AU - Musso, Camila Manso

AU - De Oliveira, João Ricardo Mendes

AU - Krepischi, Ana C.V.

AU - Vianna-Morgante, Angela Maria

AU - Zatz, Mayana

PY - 2019/8/1

Y1 - 2019/8/1

N2 - Background: Hereditary primary microcephaly (MCPH) is mainly characterised by decreased occipitofrontal circumference and variable degree of intellectual disability. MCPH with a dominant pattern of inheritance is a rare condition, so far causally linked to pathogenic variants in the ALFY, DPP6, KIF11 and DYRK1A genes. Objective: This study aimed at identifying the causative variant of the autosomal dominant form of MCPH in a Brazilian family with three affected members. Methods: Following clinical evaluation of two sibs and their mother presenting with autosomal dominant MCPH, array comparative genome hybridisation was performed using genomic DNA from peripheral blood of the family members. Gene and protein expression studies were carried out in cultured skin fibroblasts. Results: A 382 kb microduplication at 10q23.31 was detected, encompassing the entire PTEN, KLLN and ATAD1 genes. PTEN haploinsufficiency has been causally associated with macrocephaly and autism spectrum disorder and, therefore, was considered the most likely candidate gene to be involved in this autosomal dominant form of MCPH. In the patients' fibroblasts, PTEN mRNA and protein were found to be overexpressed, and the phosphorylation patterns of upstream and downstream components of the mammalian target of rapamycin (mTOR) signalling pathway were dysregulated. Conclusions: Taken together, our results demonstrate that the identified submicroscopic 10q23.31 duplication in a family with MCPH leads to markedly increased expression of PTEN and reduced activity of the mTOR signalling pathway. These results suggest that the most probable pathomechanism underlying the microcephaly phenotype in this family involves downregulation of the mTOR pathway through overexpression of PTEN.

AB - Background: Hereditary primary microcephaly (MCPH) is mainly characterised by decreased occipitofrontal circumference and variable degree of intellectual disability. MCPH with a dominant pattern of inheritance is a rare condition, so far causally linked to pathogenic variants in the ALFY, DPP6, KIF11 and DYRK1A genes. Objective: This study aimed at identifying the causative variant of the autosomal dominant form of MCPH in a Brazilian family with three affected members. Methods: Following clinical evaluation of two sibs and their mother presenting with autosomal dominant MCPH, array comparative genome hybridisation was performed using genomic DNA from peripheral blood of the family members. Gene and protein expression studies were carried out in cultured skin fibroblasts. Results: A 382 kb microduplication at 10q23.31 was detected, encompassing the entire PTEN, KLLN and ATAD1 genes. PTEN haploinsufficiency has been causally associated with macrocephaly and autism spectrum disorder and, therefore, was considered the most likely candidate gene to be involved in this autosomal dominant form of MCPH. In the patients' fibroblasts, PTEN mRNA and protein were found to be overexpressed, and the phosphorylation patterns of upstream and downstream components of the mammalian target of rapamycin (mTOR) signalling pathway were dysregulated. Conclusions: Taken together, our results demonstrate that the identified submicroscopic 10q23.31 duplication in a family with MCPH leads to markedly increased expression of PTEN and reduced activity of the mTOR signalling pathway. These results suggest that the most probable pathomechanism underlying the microcephaly phenotype in this family involves downregulation of the mTOR pathway through overexpression of PTEN.

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KW - molecular genetics

KW - neurodevelopmental disorders

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