Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

Keynote webinar | Spotlight on medication adherence

LIVE: Thursday 27th June 2024, 18:00-19:30 (CEST)
Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.
ADVANCED SEARCH
Log in
Top
Molecular Autism
Published in: Molecular Autism 1/2021

Open Access 01-12-2021 | Autism Spectrum Disorder | Research

Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism

Authors: Thomas W. Frazier, Ritika Jaini, Robyn M. Busch, Matthew Wolf, Tammy Sadler, Patricia Klaas, Antonio Y. Hardan, Julian A. Martinez-Agosto, Mustafa Sahin, Charis Eng, the Developmental Synaptopathies Consortium

Published in: Molecular Autism | Issue 1/2021

Login to get access

Abstract

Background

PTEN is a well-established risk gene for autism spectrum disorder (ASD). Yet, little is known about how PTEN mutations and associated molecular processes influence neurobehavioral function in mutation carriers with (PTEN-ASD) and without ASD (PTEN no-ASD). The primary aim of the present study was to examine group differences in peripheral blood-derived PTEN pathway protein levels between PTEN-ASD, PTEN no-ASD, and idiopathic macrocephalic ASD patients (macro-ASD). Secondarily, associations between protein levels and neurobehavioral functions were examined in the full cohort.

Methods

Patients were recruited at four tertiary medical centers. Peripheral blood-derived protein levels from canonical PTEN pathways (PI3K/AKT and MAPK/ERK) were analyzed using Western blot analyses blinded to genotype and ASD status. Neurobehavioral measures included standardized assessments of global cognitive ability and multiple neurobehavioral domains. Analysis of variance models examined group differences in demographic, neurobehavioral, and protein measures. Bivariate correlations, structural models, and statistical learning procedures estimated associations between molecular and neurobehavioral variables. To complement patient data, Western blots for downstream proteins were generated to evaluate canonical PTEN pathways in the PTEN-m3m4 mouse model.

Results

Participants included 61 patients (25 PTEN-ASD, 16 PTEN no-ASD, and 20 macro-ASD). Decreased PTEN and S6 were observed in both PTEN mutation groups. Reductions in MnSOD and increases in P-S6 were observed in ASD groups. Elevated neural P-AKT/AKT and P-S6/S6 from PTEN murine models parallel our patient observations. Patient PTEN and AKT levels were independently associated with global cognitive ability, and p27 expression was associated with frontal sub-cortical functions. As a group, molecular measures added significant predictive value to several neurobehavioral domains over and above PTEN mutation status.

Limitations

Sample sizes were small, precluding within-group analyses. Protein and neurobehavioral data were limited to a single evaluation. A small number of patients were excluded with invalid protein data, and cognitively impaired patients had missing data on some assessments.

Conclusions

Several canonical PTEN pathway molecules appear to influence the presence of ASD and modify neurobehavioral function in PTEN mutation patients. Protein assays of the PTEN pathway may be useful for predicting neurobehavioral outcomes in PTEN patients. Future longitudinal analyses are needed to replicate these findings and evaluate within-group relationships between protein and neurobehavioral measures.

Trial registration

ClinicalTrials.gov Identifier NCT02461446
Appendix
Available only for authorised users
Literature
1.
2.
van Diepen MT, Eickholt BJ. Function of PTEN during the formation and maintenance of neuronal circuits in the brain. Dev Neurosci. 2008;30(1–3):59–64.PubMedCrossRef
3.
Delatycki MB, Danks A, Churchyard A, Zhou X-P, Eng C. De novo germline PTEN mutation in a man with Lhermitte–Duclos disease which arose on the paternal chromosome and was transmitted to his child with polydactyly and Wormian bones. J Med Genet. 2003;40:e92.PubMedPubMedCentralCrossRef
4.
5.
Buxbaum JDC, Cai G, Chaste P, Nygren G, Goldsmith J, Reichert J, Anckarsäter H, et al. Mutation screening of the PTEN gene in patients with autism spectrum disorders and macrocephaly. Am J Med Genet Part B N(europsychiatric Genet). 2007;144:484–91.CrossRef
6.
Butler MG, Dasouki MJ, Zhou X-P, Talebizadeh Z, Brown M, Takahashi TN, et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet. 2005;42:318–21.PubMedPubMedCentralCrossRef
7.
8.
McBride KL, Varga EA, Pastore MT, Prior TW, Manickam K, Atkin JF, et al. Confirmation study of PTEN mutations among individuals with autism or developmental delays/mental retardation and macrocephaly. Autism Res. 2010;3(3):137–41.CrossRefPubMed
9.
Orrico A, Galli L, Buoni S, Orsi A, Vonella G, Sorrentino V. Novel PTEN mutations in neurodevelopmental disorders and macrocephaly. Clin Genet. 2009;75(2):195–8.PubMedCrossRef
10.
Varga EA, Pastore M, Prior T, Herman GE, McBride KL. The prevalence of PTEN mutations in a clinical pediatric cohort with autism spectrum disorders, developmental delay, and macrocephaly. Genet Med. 2009;11(2):111–7.CrossRefPubMed
11.
Hobert JA, Embacher R, Mester JL, Frazier TW, Eng C. Biochemical screening and PTEN mutation analysis in individuals with autism spectrum disorders and macrocephaly. Eur J Hum Genet. 2014;22(2):273–6.CrossRefPubMed
12.
Herman GE, Butter E, Enrile B, Pastore M, Prior TW, Sommer A. Increasing knowledge of PTEN germline mutations: two additional patients with autism and macrocephaly. Am J Med Genet. 2007;143A:589–93.PubMedCrossRef
13.
Tilot AK, Frazier TW 2nd, Eng C. Balancing proliferation and connectivity in PTEN-associated autism spectrum disorder. Neurotherapeutics. 2015;12(3):609–19.PubMedPubMedCentralCrossRef
14.
Yuen RK, Merico D, Bookman M, Howe JL, Thiruvahindrapuram B, Patel RV, et al. Whole genome sequencing resource identifies 18 new candidate genes for autism spectrum disorder. Nat Neurosci. 2017;20(4):602–11.PubMedCentralCrossRef
15.
Iossifov I, O’Roak BJ, Sanders SJ, Ronemus M, Krumm N, Levy D, et al. The contribution of de novo coding mutations to autism spectrum disorder. Nature. 2014;515(7526):216–21.PubMedPubMedCentralCrossRef
16.
O’Roak BJ, Stessman HA, Boyle EA, Witherspoon KT, Martin B, Lee C, et al. Recurrent de novo mutations implicate novel genes underlying simplex autism risk. Nat Commun. 2014;5:5595.PubMedCrossRef
17.
Trost B, Engchuan W, Nguyen CM, Thiruvahindrapuram B, Dolzhenko E, Backstrom I, et al. Genome-wide detection of tandem DNA repeats that are expanded in autism. Nature. 2020;586(7827):80–6.PubMedCrossRef
18.
Sanders SJ, Murtha MT, Gupta AR, Murdoch JD, Raubeson MJ, Willsey AJ, et al. De novo mutations revealed by whole-exome sequencing are strongly associated with autism. Nature. 2012;485(7397):237–41.PubMedPubMedCentralCrossRef
19.
Tammimies K, Marshall CR, Walker S, Kaur G, Thiruvahindrapuram B, Lionel AC, et al. Molecular diagnostic yield of chromosomal microarray analysis and whole-exome sequencing in children with autism spectrum disorder. JAMA. 2015;314(9):895–903.PubMedCrossRef
20.
Schaaf CP, Betancur C, Yuen RKC, Parr JR, Skuse DH, Gallagher L, et al. A framework for an evidence-based gene list relevant to autism spectrum disorder. Nat Rev Genet. 2020;21(6):367–76.PubMedCrossRef
21.
Hansen-Kiss E, Beinkampen S, Adler B, Frazier T, Prior T, Erdman S, et al. A retrospective chart review of the features of PTEN hamartoma tumour syndrome in children. J Med Genet. 2017;54(7):471–8.PubMedCrossRef
22.
Ciaccio C, Saletti V, D’Arrigo S, Esposito S, Alfei E, Moroni I, et al. Clinical spectrum of PTEN mutation in pediatric patients. A bicenter experience. Eur J Med Genet. 2018;62:103596.PubMedCrossRef
23.
Amiri A, Cho W, Zhou J, Birnbaum SG, Sinton CM, McKay RM, et al. Pten deletion in adult hippocampal neural stem/progenitor cells causes cellular abnormalities and alters neurogenesis. J Neurosci. 2012;32(17):5880–90.PubMedPubMedCentralCrossRef
24.
Fraser MM, Zhu X, Kwon CH, Uhlmann EJ, Gutmann DH, Baker SJ. Pten loss causes hypertrophy and increased proliferation of astrocytes in vivo. Cancer Res. 2004;64(21):7773–9.PubMedCrossRef
25.
Kwon CH, Luikart BW, Powell CM, Zhou J, Matheny SA, Zhang W, et al. Pten regulates neuronal arborization and social interaction in mice. Neuron. 2006;50:377–88.PubMedPubMedCentralCrossRef
26.
Kwon CH, Zhu X, Zhang J, Knoop LL, Tharp R, Smeyne RJ, et al. Pten regulates neuronal soma size: a mouse model of Lhermitte–Duclos disease. Nat Genet. 2001;29(4):404–11.PubMedCrossRef
27.
Page DT, Kuti OJ, Prestia C, Sur M. Haploinsufficiency for Pten and Serotonin transporter cooperatively influences brain size and social behavior. Proc Natl Acad Sci USA. 2009;106(6):1989–94.CrossRefPubMedPubMedCentral
28.
Tilot AK, Bebek G, Niazi F, Altemus JB, Romigh T, Frazier TW, et al. Neural transcriptome of constitutional Pten dysfunction in mice and its relevance to human idiopathic autism spectrum disorder. Mol Psychiatry. 2016;21:118–25.PubMedCrossRef
29.
Tilot AK, Gaugler MK, Yu Q, Romigh T, Yu W, Miller RH, et al. Germline disruption of Pten localization causes enhanced sex-dependent social motivation and increased glial production. Hum Mol Genet. 2014;23(12):3212–27.PubMedPubMedCentralCrossRef
30.
31.
Just MA, Cherkassky VL, Keller TA, Kana RK, Minshew NJ. Functional and anatomical cortical underconnectivity in autism: evidence from an FMRI study of an executive function task and corpus callosum morphometry. Cereb Cortex. 2007;17(4):951–61.PubMedCrossRef
32.
Fishman I, Keown CL, Lincoln AJ, Pineda JA, Muller RA. Atypical cross talk between mentalizing and mirror neuron networks in autism spectrum disorder. JAMA Psychiatry. 2014;71(7):751–60.PubMedPubMedCentralCrossRef
33.
Frazier TW, Embacher R, Tilot AK, Koenig K, Mester J, Eng C. Molecular and phenotypic abnormalities in individuals with germline heterozygous PTEN mutations and autism. Mol Psychiatry. 2015;20(9):1132–8.PubMedCrossRef
34.
Busch RM, Chapin JS, Mester J, Ferguson L, Haut JS, Frazier TW, et al. Cognitive characteristics of PTEN hamartoma tumor syndromes. Genet Med. 2013;15(7):548–53.PubMedPubMedCentralCrossRef
35.
Busch RM, Srivastava S, Hogue O, Frazier TW, Klaas P, Hardan A, et al. Neurobehavioral phenotype of autism spectrum disorder associated with germline heterozygous mutations in PTEN. Transl Psychiatry. 2019;9(1):253.PubMedPubMedCentralCrossRef
36.
Muhle RA, Reed HE, Stratigos KA, Veenstra-VanderWeele J. The emerging clinical neuroscience of autism spectrum disorder: a review. JAMA Psychiatry. 2018;75(5):514–23.PubMedCrossRef
37.
Hoang N, Cytrynbaum C, Scherer SW. Communicating complex genomic information: a counselling approach derived from research experience with autism spectrum disorder. Patient Educ Couns. 2018;101(2):352–61.PubMedCrossRef
38.
Tan MH, Mester J, Peterson C, Yang Y, Chen JL, Rybicki LA, et al. A clinical scoring system for selection of patients for PTEN mutation testing is proposed on the basis of a prospective study of 3042 probands. Am J Hum Genet. 2012;88(1):42–56.CrossRef
39.
Jaini R, Loya MG, King AT, Thacker S, Sarn NB, Yu Q, et al. Germline PTEN mutations are associated with a skewed peripheral immune repertoire in humans and mice. Hum Mol Genet. 2020;29(14):2353–64.PubMedCrossRefPubMedCentral
40.
41.
Little RJ, Rubin DB. Statistical analysis with missing data. 2nd ed. New York: Wiley; 2002.CrossRef
42.
Schafer JL, Graham JW. Missing data: our view of the state of the art. Psychol Methods. 2002;7(2):147–77.PubMedCrossRef
43.
44.
Muthén BO, Muthén LK, Asparouhov T. Regression and mediation analysis using MPlus. Los Angeles: Muthén & Muthén; 2016.
45.
Corp IBM. IBM SPSS Statistics for Windows. 260th ed. Armonk: IBM Corp; 2018.
46.
Muthén LK, Muthén BO. Mplus User’s Guide. 7th ed. Los Angeles: Muthén & Muthén; 1998.
47.
Zablotsky B, Black LI, Maenner MJ, Schieve LA, Danielson ML, Bitsko RH, et al. Prevalence and trends of developmental disabilities among children in the united states: 2009–2017. Pediatrics. 2019;144(4):e20190811.PubMedCrossRef
48.
Mighell TL, Evans-Dutson S, O’Roak BJ. A saturation mutagenesis approach to understanding PTEN lipid phosphatase activity and genotype-phenotype relationships. Am J Hum Genet. 2018;102(5):943–55.PubMedPubMedCentralCrossRef
49.
Matreyek KA, Starita LM, Stephany JJ, Martin B, Chiasson MA, Gray VE, et al. Multiplex assessment of protein variant abundance by massively parallel sequencing. Nat Genet. 2018;50(6):874–82.PubMedPubMedCentralCrossRef
50.
Papa A, Wan L, Bonora M, Salmena L, Song MS, Hobbs RM, et al. Cancer-associated PTEN mutants act in a dominant-negative manner to suppress PTEN protein function. Cell. 2014;157(3):595–610.PubMedPubMedCentralCrossRef
51.
Post KL, Belmadani M, Ganguly P, Meili F, Dingwall R, McDiarmid TA, et al. Multi-model functionalization of disease-associated PTEN missense mutations identifies multiple molecular mechanisms underlying protein dysfunction. Nat Commun. 2020;11(1):2073.PubMedPubMedCentralCrossRef
52.
Ganesan H, Balasubramanian V, Iyer M, Venugopal A, Subramaniam MD, Cho SG, et al. mTOR signalling pathway—a root cause for idiopathic autism? BMB Rep. 2019;52(7):424–33.PubMedPubMedCentralCrossRef
53.
Yehia L, Seyfi M, Niestroj LM, Padmanabhan R, Ni Y, Frazier TW, et al. Copy number variation and clinical outcomes in patients with germline PTEN mutations. JAMA Netw Open. 2020;3(1):e1920415.PubMedPubMedCentralCrossRef
54.
Yehia L, Ni Y, Feng F, Seyfi M, Sadler T, Frazier TW, et al. Distinct alterations in tricarboxylic acid cycle metabolites associate with cancer and autism phenotypes in cowden syndrome and Bannayan–Riley–Ruvalcaba syndrome. Am J Hum Genet. 2019;105(4):813–21.PubMedPubMedCentralCrossRef
55.
Kern JK, Jones AM. Evidence of toxicity, oxidative stress, and neuronal insult in autism. J Toxicol Environ Health Part B. 2006;9(6):485–99.CrossRef
56.
Abruzzo PM, Matte A, Bolotta A, Federti E, Ghezzo A, Guarnieri T, et al. Plasma peroxiredoxin changes and inflammatory cytokines support the involvement of neuro-inflammation and oxidative stress in Autism Spectrum Disorder. J Transl Med. 2019;17(1):332.PubMedPubMedCentralCrossRef
57.
Rossignol DA, Frye RE. Mitochondrial dysfunction in autism spectrum disorders: a systematic review and meta-analysis. Mol Psychiatry. 2012;17(3):290–314.PubMedCrossRef
58.
Weissman JR, Kelley RI, Bauman ML, Cohen BH, Murray KF, Mitchell RL, et al. Mitochondrial disease in autism spectrum disorder patients: a cohort analysis. PLoS ONE. 2008;3(11):e3815.PubMedPubMedCentralCrossRef
59.
Yenkoyan K, Harutyunyan H, Harutyunyan A. A certain role of SOD/CAT imbalance in pathogenesis of autism spectrum disorders. Free Radic Biol Med. 2018;123:85–95.PubMedCrossRef
60.
Smith AM, Natowicz MR, Braas D, Ludwig MA, Ney DM, Donley ELR, et al. A metabolomics approach to screening for autism risk in the children’s autism metabolome project. Autism Res. 2020;13(8):1270–85.PubMedPubMedCentralCrossRef
61.
Lustgarten MS, Jang YC, Liu Y, Qi W, Qin Y, Dahia PL, et al. MnSOD deficiency results in elevated oxidative stress and decreased mitochondrial function but does not lead to muscle atrophy during aging. Aging Cell. 2011;10(3):493–505.PubMedCrossRef
62.
Larson JC, Mostofsky SH. Motor deficits in autism. In: Tuchman R, Rapin I, editors. Autism: a neurological disorder of early brain development. London: Mac Keith Press; 2006.
63.
Dewey D, Cantell M, Crawford SG. Motor and gestural performance in children with autism spectrum disorders, developmental coordination disorder, and/or attention deficit hyperactivity disorder. J Int Neuropsychol Soc. 2007;13(2):246–56.PubMedCrossRef
64.
Licari MK, Alvares GA, Varcin K, Evans KL, Cleary D, Reid SL, et al. Prevalence of motor difficulties in autism spectrum disorder: analysis of a population-based cohort. Autism Res. 2020;13(2):298–306.PubMedCrossRef
65.
66.
Hooshmandi M, Wong C, Khoutorsky A. Dysregulation of translational control signaling in autism spectrum disorders. Cell Signal. 2020;75:109746.PubMedCrossRef
67.
Hazlett HC, Gu H, Munsell BC, Kim SH, Styner M, Wolff JJ, et al. Early brain development in infants at high risk for autism spectrum disorder. Nature. 2017;542(7641):348–51.PubMedPubMedCentralCrossRef
68.
Piven J, Elison JT, Zylka MJ. Toward a conceptual framework for early brain and behavior development in autism. Mol Psychiatry. 2018;23(1):165.PubMedCrossRef
69.
Lainhart JE. Increased rate of head growth during infancy in autism. J Am Med Assoc. 2003;290:393–4.CrossRef
70.
Lainhart JE, Bigler ED, Bocian M, Coon H, Dinh E, Dawson G, et al. Head circumference and height in autism: a study by the collaborative program of excellence in autism. Am J Med Genet A. 2006;140(21):2257–74.PubMedPubMedCentralCrossRef
71.
Winden KD, Ebrahimi-Fakhari D, Sahin M. Abnormal mTOR activation in autism. Annu Rev Neurosci. 2018;41:1–23.PubMedCrossRef
72.
Zhang J, Gao Z, Ye J. Phosphorylation and degradation of S6K1 (p70S6K1) in response to persistent JNK1 activation. Biochim Biophys Acta. 2013;1832(12):1980–8.PubMedCrossRef
Metadata
Title
Cross-level analysis of molecular and neurobehavioral function in a prospective series of patients with germline heterozygous PTEN mutations with and without autism
Authors
Thomas W. Frazier
Ritika Jaini
Robyn M. Busch
Matthew Wolf
Tammy Sadler
Patricia Klaas
Antonio Y. Hardan
Julian A. Martinez-Agosto
Mustafa Sahin
Charis Eng
the Developmental Synaptopathies Consortium
Publication date
01-12-2021
Publisher
BioMed Central
Published in
Molecular Autism / Issue 1/2021
Electronic ISSN: 2040-2392
DOI
https://doi.org/10.1186/s13229-020-00406-6

Other articles of this Issue 1/2021

Molecular Autism 1/2021 Go to the issue

Research

Childhood diagnoses in individuals identified as autistics in adulthood

Methodology

Application of Airy beam light sheet microscopy to examine early neurodevelopmental structures in 3D hiPSC-derived human cortical spheroids

Research

Analysis of common genetic variation and rare CNVs in the Australian Autism Biobank

Research

Extremely preterm birth and autistic traits in young adulthood: the EPICure study

Research

Single-participant structural similarity matrices lead to greater accuracy in classification of participants than function in autism in MRI

Research

Autism-associated biomarkers: test–retest reliability and relationship to quantitative social trait variation in rhesus monkeys