Toward better characterization of restricted and repetitive behaviors in individuals with germline heterozygous PTEN mutations.
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ABSTRACT:
SUBMITTER: Uljarevic M
PROVIDER: S-EPMC8530948 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:PTEN is a tumor suppressor associated with an inherited cancer syndrome and an important regulator of ongoing neural connectivity and plasticity. The present study examined molecular and phenotypic characteristics of individuals with germline heterozygous PTEN mutations and autism spectrum disorder (ASD) (PTEN-ASD), with the aim of identifying pathophysiologic markers that specifically associate with PTEN-ASD and that may serve as targets for future treatment trials. PTEN-ASD patients (n=17) were compared with idiopathic (non-PTEN) ASD patients with (macro-ASD, n=16) and without macrocephaly (normo-ASD, n=38) and healthy controls (n=14). Group differences were evaluated for PTEN pathway protein expression levels, global and regional structural brain volumes and cortical thickness measures, neurocognition and adaptive behavior. RNA expression patterns and brain characteristics of a murine model of Pten mislocalization were used to further evaluate abnormalities observed in human PTEN-ASD patients. PTEN-ASD had a high proportion of missense mutations and showed reduced PTEN protein levels. Compared with the other groups, prominent white-matter and cognitive abnormalities were specifically associated with PTEN-ASD patients, with strong reductions in processing speed and working memory. White-matter abnormalities mediated the relationship between PTEN protein reductions and reduced cognitive ability. The Pten(m3m4) murine model had differential expression of genes related to myelination and increased corpus callosum. Processing speed and working memory deficits and white-matter abnormalities may serve as useful features that signal clinicians that PTEN is etiologic and prompting referral to genetic professionals for gene testing, genetic counseling and cancer risk management; and could reveal treatment targets in trials of treatments for PTEN-ASD.
| S-EPMC4388743 | biostudies-literature
Project description:Age-adjusted cancer incidence and age-related penetrance studies have helped guide cancer risk assessment and management. PTEN hamartoma tumor syndrome (PHTS) is a term encompassing subsets of several clinical syndromes with germline mutations in the PTEN tumor suppressor gene. We conducted the first prospective study to clarify corresponding cancer risks to shed biologic insights on human germline PTEN mutations, and to better inform current surveillance recommendations on the basis of expert opinion.A series of 3,399 individuals meeting relaxed International Cowden Consortium PHTS criteria were prospectively recruited; 368 individuals were found to have deleterious germline PTEN mutations. Age-adjusted standardized incidence ratio (SIR) calculations and genotype-phenotype analyses were carried out.Elevated SIRs were found for carcinomas of the breast [25.4, 95% confidence interval (CI), 19.8-32.0], thyroid (51.1, 38.1-67.1), endometrium (42.9, 28.1-62.8), colorectum (10.3, 5.6-17.4), kidney (30.6, 17.8-49.4), and melanoma (8.5, 4.1-15.6). Estimated lifetime risks were, respectively, 85.2% (95% CI, 71.4%-99.1%), 35.2% (19.7%-50.7%), 28.2% (17.1%-39.3%), 9.0% (3.8%-14.1%), 33.6% (10.4%-56.9%), and 6% (1.6%-9.4%). Promoter mutations were associated with breast cancer, whereas colorectal cancer was associated with nonsense mutations.Lifetime risks for a variety of cancers, now extending to colorectal cancer, kidney cancer, and melanoma, are increased in patients with PTEN mutations. The genotype-phenotype associations here may provide new insights on PTEN structure and function. We propose a comprehensive approach to surveillance of patients with PTEN mutations.
| S-EPMC3261579 | biostudies-literature
Project description:Germline mutations in PTEN, the gene that encodes phosphatase and tensin homolog, have been identified in up to 20% of children with autism spectrum disorder (ASD) and macrocephaly and are associated with marked abnormalities in the white matter of the brain. This study sought to characterize the neurobehavioral phenotype of PTEN-ASD. Comprehensive neurobehavioral evaluations were conducted in 36 participants (ages 3-21 years) with PTEN-ASD and compared to two groups of controls: non-syndromic ASD with macrocephaly (Macro-ASD, n = 25) and those with PTEN mutations without ASD (PTEN-no ASD, n = 23). Linear regression analysis or Kruskal-Wallis tests were used to examine group differences on neurobehavioral measures (cognitive, behavioral, sensory, and adaptive functioning) and, for select measures, one-sample t-tests were used to compare group performance to healthy control norms. These analyses revealed a distinct neuropsychological profile associated with mutations in PTEN suggesting primary disruption of frontal lobe systems (i.e., attention, impulsivity, reaction time, processing speed, and motor coordination). Cognitive deficits in PTEN-ASD are more severe than those in PTEN-no ASD and extend to other areas of neurobehavioral function, specifically, adaptive behavior and sensory deficits. While core ASD symptoms are similar in PTEN-ASD and Macro-ASD, PTEN-ASD had lower clinical ratings of autism severity and showed more sensory abnormalities suggestive of less sensory responsiveness. Together, these results suggest that PTEN-ASD has a distinct neurobehavioral phenotype compared to idiopathic ASD that is likely to warrant special consideration for overall assessment and treatment.
| S-EPMC6783427 | biostudies-literature
Project description:BackgroundRestricted and repetitive behaviors (RRBs) are core features of autism spectrum disorder (ASD) and one of the earliest behavioral signs of ASD. However, RRBs are also present in typically developing (TD) infants, toddlers, and preschool-aged children. Past work suggests that examining change in these behaviors over time is essential to distinguish between normative manifestations of these behaviors and behaviors that denote risk for a neurodevelopmental disorder. One challenge in examining changes in these behaviors over time is that most measures of RRBs have not established longitudinal measurement invariance. The aims of this study were to (1) establish measurement invariance in the Repetitive Behavior Scales for Early Childhood (RBS-EC), a parent-report questionnaire of RRBs, and (2) model developmental change in RRBs from 8 to 36 months.MethodsWe collected RBS-EC responses from parents of TD infants (n = 180) from 8 to 36 months (n = 606 responses, with participants contributing an average of 3-time points). We leverage a novel methodological approach to measurement invariance testing (Bauer, Psychological Models, 22(3), 507-526, 2017), moderated nonlinear factor analysis (MNLFA), to determine whether the RBS-EC was invariant across age and sex. We then generated adjusted factor score estimates for each subscale of the RBS-EC (repetitive motor, self-directed, and higher-order behaviors), and used linear mixed effects models to estimate between- and within-person changes in the RBS-EC over time.ResultsThe RBS-EC showed some non-invariance as a function of age. We were able to adjust for this non-invariance in order to more accurately model changes in the RBS-EC over time. Repetitive motor and self-directed behaviors showed a linear decline from 8 to 36 months, while higher-order behaviors showed a quadratic trajectory such that they began to decline later in development at around 18 months. Using adjusted factor scores as opposed to unadjusted raw mean scores provided a number of benefits, including increased within-person variability and precision.ConclusionsThe RBS-EC is sensitive enough to measure the presence of RRBs in a TD sample, as well as their decline with age. Using factor score estimates of each subscale adjusted for non-invariance allowed us to more precisely estimate change in these behaviors over time.
| S-EPMC7798225 | biostudies-literature
Project description:KCNQ/Kv 7 channels conduct voltage-dependent outward potassium currents that potently decrease neuronal excitability. Heterozygous inherited mutations in their principle subunits Kv 7.2/KCNQ2 and Kv 7.3/KCNQ3 cause benign familial neonatal epilepsy whereas patients with de novo heterozygous Kv 7.2 mutations are associated with early-onset epileptic encephalopathy and neurodevelopmental disorders characterized by intellectual disability, developmental delay and autism. However, the role of Kv 7.2-containing Kv 7 channels in behaviors especially autism-associated behaviors has not been described. Because pathogenic Kv 7.2 mutations in patients are typically heterozygous loss-of-function mutations, we investigated the contributions of Kv 7.2 to exploratory, social, repetitive and compulsive-like behaviors by behavioral phenotyping of both male and female KCNQ2+/- mice that were heterozygous null for the KCNQ2 gene. Compared with their wild-type littermates, male and female KCNQ2+/- mice displayed increased locomotor activity in their home cage during the light phase but not the dark phase and showed no difference in motor coordination, suggesting hyperactivity during the inactive light phase. In the dark phase, KCNQ2+/- group showed enhanced exploratory behaviors, and repetitive grooming but decreased sociability with sex differences in the degree of these behaviors. While male KCNQ2+/- mice displayed enhanced compulsive-like behavior and social dominance, female KCNQ2+/- mice did not. In addition to elevated seizure susceptibility, our findings together indicate that heterozygous loss of Kv 7.2 induces behavioral abnormalities including autism-associated behaviors such as reduced sociability and enhanced repetitive behaviors. Therefore, our study is the first to provide a tangible link between loss-of-function Kv 7.2 mutations and the behavioral comorbidities of Kv 7.2-associated epilepsy.
| S-EPMC7050516 | biostudies-literature
Project description:Cowden syndrome (CS) or multiple hamartoma syndrome (MIM 158350) is an autosomal dominant disorder with an increased risk for breast and thyroid carcinoma. The diagnosis of CS, as operationally defined by the International Cowden Consortium, is made when a patient, or family, has a combination of pathognomonic major and/or minor criteria. The CS gene has recently been identified as PTEN, which maps at 10q23.3 and encodes a dual specificity phosphatase. PTEN appears to function as a tumour suppressor in CS, with between 13-80% of CS families harbouring germline nonsense, missense, and frameshift mutations predicted to disrupt normal PTEN function. To date, only a small number of tumour suppressor genes, including BRCA1, BRCA2, and p53, have been associated with familial breast or breast/ovarian cancer families. Given the involvement of PTEN in CS, we postulated that PTEN was a likely candidate to play a role in families with a "CS-like" phenotype, but not classical CS. To answer these questions, we gathered a series of patients from families who had features reminiscent of CS but did not meet the Consortium Criteria. Using a combination of denaturing gradient gel electrophoresis (DGGE), temporal temperature gel electrophoresis (TTGE), and sequence analysis, we screened 64 unrelated CS-like subjects for germline mutations in PTEN. A single male with follicular thyroid carcinoma from one of these 64 (2%) CS-like families harboured a germline point mutation, c.209T-->C. This mutation occurred at the last nucleotide of exon 3 and within a region homologous to the cytoskeletal proteins tensin and auxilin. We conclude that germline PTEN mutations play a relatively minor role in CS-like families. In addition, our data would suggest that, for the most part, the strict International Cowden Consortium operational diagnostic criteria for CS are quite robust and should remain in place.
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Project description:Cowden syndrome (multiple hamartoma syndrome, MIM 158350) is an early onset syndrome characterized by multiple hamartomas in the skin, mucous membranes, breast, thyroid and endometrium. Patients with Cowden syndrome have increased risk of breast cancer, thyroid cancer and endometrial cancer. In 1997 germline mutations in PTEN were demonstrated to cause Cowden syndrome. We report the results of diagnostic and predictive testing in all families with Cowden syndrome or suspected Cowden syndrome registered at the Norwegian cancer family clinics. PTEN mutations were found in all six families meeting the clinical criteria for Cowden syndrome, in none of the two families assumed to have Cowden syndrome but not fulfilling the criteria, and in none of the eight families selected in our computerized medical files to have a combination of breast and thyroid cancers. Age-related penetrances for the various neoplasms are given. All families but one were small and de novo mutations were found.
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Project description:Approximately 0.5%-1% of the general population has been estimated to be heterozygous for a germline mutation in the ATM gene. Mutations in the ATM gene are responsible for the autosomal recessive disorder ataxia-telangiectasia (A-T) (MIM 208900). The finding that ATM-heterozygotes have an increased relative risk for breast cancer was supported by some studies but not confirmed by others. In view of this discrepancy, we examined the frequency of ATM germline mutations in a selected group of Dutch patients with breast cancer. We have analyzed ATM germline mutations in normal blood lymphocytes, using the protein-truncation test followed by genomic-sequence analysis. A high percentage of ATM germline mutations was demonstrated among patients with sporadic breast cancer. The 82 patients included in this study had developed breast cancer at age <45 and had survived >/=5 years (mean 15 years), and in 33 (40%) of the patients a contralateral breast tumor had been diagnosed. Among these patients we identified seven (8.5%) ATM germline mutations, of which five are distinct. One splice-site mutation (IVS10-6T-->G) was detected three times in our series. Four heterozygous carriers were patients with bilateral breast cancer. Our results indicate that the mutations identified in this study are "A-T disease-causing" mutations that might be associated with an increased risk of breast cancer in heterozygotes. We conclude that ATM heterozygotes have an approximately ninefold-increased risk of developing a type of breast cancer characterized by frequent bilateral occurrence, early age at onset, and long-term survival. The specific characteristics of our population of patients may explain why such a high frequency was not found in other series.
| S-EPMC1288102 | biostudies-literature
Project description:Familial adenomatous polyposis (FAP) is an inherited syndrome caused by a heterozygous adenomatous polyposis coli (APC) germline mutation, associated with a profound lifetime risk for colorectal cancer. While it is well accepted that tumorigenic transformation is initiated following acquisition of a second mutation and loss of function of the APC gene, the role of heterozygous APC mutation in this process is yet to be discovered. This work aimed to explore whether a heterozygous APC mutation induces molecular defects underlying tumorigenic transformation and how different APC germline mutations predict disease severity. Three FAP-human embryonic stem cell lines (FAP1/2/3-hESC lines) carrying germline mutations at different locations of the APC gene, and two control hESC lines free of the APC mutation, were differentiated into colon organoids and analyzed by immunohistochemistry and RNA sequencing. In addition, data regarding the genotype and clinical phenotype of the embryo donor parents were collected from medical records. FAP-hESCs carrying a complete loss-of-function of a single APC allele (FAP3) generated complex and molecularly mature colon organoids, which were similar to controls. In contrast, FAP-hESCs carrying APC truncation mutations (FAP1 and FAP2) generated only few cyst-like structures and cell aggregates of various shape, occasionally with luminal parts, which aligned with their failure to upregulate critical differentiation genes early in the process, as shown by RNA sequencing. Abnormal disease phenotype was shown also in non-pathological colon of FAP patients by the randomly distribution of proliferating cells throughout the crypts, compared to their focused localization in the lower part of the crypt in healthy/non-FAP patients. Genotype/phenotype analysis revealed correlations between the colon organoid maturation potential and FAP severity in the carrier parents. In conclusion, this study suggest that a single truncated APC allele is sufficient to initiate early molecular tumorigenic activity. In addition, the results hint that patient-specific hESC-derived colon organoids can probably predict disease severity among FAP patients.
| S-EPMC7933349 | biostudies-literature
Project description:Differentiated thyroid cancer (DTC) is seen in 3%-10% of individuals carrying a germline PTEN mutation. Patients with PTEN mutations are at risk for additional neoplasms as are their affected offspring. However, the frequency of PTEN mutations among DTC cases has not been systematically analyzed. The objective of this study was to determine the frequency of PTEN mutations in an unselected group of patients with DTC and to identify whether additional clinical features might indicate the need for referral for genetic counseling and possible testing.We collected personal medical and family history information, head circumference data, and blood from 259 consecutively identified clinic-based patients with DTC, unselected for personal or family history. Individuals were categorized for diagnostic criteria for Cowden syndrome (CS) using the 2009 National Comprehensive Cancer Network (NCCN) guidelines and underwent germline PTEN mutation analysis.Two of the 259 patients (0.8%), with both follicular thyroid carcinoma and macrocephaly, were found to carry a germline mutation in the PTEN gene. The PTEN mutation frequency in unselected cases of follicular thyroid carcinoma was 4.8%.The frequency of germline pathogenic PTEN mutations in an unselected series of patients with DTC is relatively low, but it is enriched by considering follicular histology and macrocephaly. These results suggest that by adding head circumference to the clinical assessment, thyroid cancer specialists can more effectively identify patients needing referral for cancer genetic services.
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