The mTOR pathway and its role in human genetic diseases

Rosner, Margit; Hanneder, Michaela; Siegel, Nicol; Valli, Alessandro; Fuchs, Christiane; Hengstschläger, Markus

doi:10.1016/j.mrrev.2008.06.001

Cited by 160 publications

(118 citation statements)

References 106 publications

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“…[15][16][17] There is marked clinical variability in both, even among relatives, and careful monitoring of children who present with cutaneous features (café au lait spots, angiofibromas) is often recommended. 15,18,19 However, monitoring would not have influenced the timing of tumor diagnosis in 3 of the 4 children with familial cancer syndromes reported in our study, because the syndrome was not diagnosed until their brain tumor symptoms began causing concern.…”

Section: Discussionmentioning

confidence: 99%

Brain Tumor Signs and Symptoms: Analysis of Primary Health Care Records From the UKCCS

et al. 2010

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WHAT'S KNOWN ON THIS SUBJECT:Good information on symptom clusters seen in secondary care at the time of brain tumor diagnosis is now available, but information on how children present in primary care is poor and subject to recall bias. WHAT THIS STUDY ADDS:This report describes signs and symptoms recorded in children's general practitioner (primary health care) records between birth and brain tumor diagnosis and for the first time, compares rates of attendance and reasons for consultation with those of unaffected children. RESULTS:On average, cases consulted more often than controls between birth and diagnosis/pseudodiagnosis with brain tumor signs and symptoms. Their consultation rate with Ն1 suggestive symptom escalated in the 2 years before diagnosis. Symptom prevalence was higher among cases than controls, a relative difference of 3.29 times as many consultations with Ն1 suggestive symptom (95% confidence interval [CI]: 2.82-3.83) and 7.01 as many with more than 1 (95% CI: 5.38 -9.13). In each 6-month period in the 4 years before diagnosis, cases had at least twice as many consultations with Ն1 suggestive symptom (20.81 times as many in the 6 months before diagnosis ) and 2-3 times more records of suggestive symptoms (28.35 times more in the 6 months before diagnosis ). Symptoms rarely or not observed among control children included head tilt, odd head movements, odd posture, back or neck stiffness, and unsteadiness without obvious cause.CONCLUSION Key to identifying the 1 child among many who merits prompt investigation is recognition of unusual symptoms, or specific symptom patterns.

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Section: Discussionmentioning

confidence: 99%

Brain Tumor Signs and Symptoms: Analysis of Primary Health Care Records From the UKCCS

et al. 2010

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“…These results, along with the high expression of DOCK7 in the developing brain (16), suggest that DOCK7 may play an important role in neurological functions. DOCK7 has also been found to interact with the tuberous sclerosis (TSC) protein, hamartin (28,29). Tuberous sclerosis is a multisystem disorder characterized by tumor-like growths, and the TSC protein complex has been shown to have GTPase activity (29).…”

Section: Discussionmentioning

confidence: 99%

“…DOCK7 has also been found to interact with the tuberous sclerosis (TSC) protein, hamartin (28,29). Tuberous sclerosis is a multisystem disorder characterized by tumor-like growths, and the TSC protein complex has been shown to have GTPase activity (29).…”

Section: Discussionmentioning

confidence: 99%

Mice with mutations of Dock7 have generalized hypopigmentation and white-spotting but show normal neurological function

Blasius¹,

Brandl²,

Crozat³

et al. 2009

Proc. Natl. Acad. Sci. U.S.A.

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The classical recessive coat color mutation misty (m) arose spontaneously on the DBA/J background and causes generalized hypopigmentation and localized white-spotting in mice, with a lack of pigment on the belly, tail tip, and paws. Here we describe moonlight (mnlt), a second hypopigmentation and white-spotting mutation identified on the C57BL/6J background, which yields a phenotypic copy of m/m coat color traits. We demonstrate that the 2 mutations are allelic. m/m and mnlt/mnlt phenotypes both result from mutations that truncate the dedicator of cytokinesis 7 protein (DOCK7), a widely expressed Rho family guanine nucleotide exchange factor. Although Dock7 is transcribed at high levels in the developing brain and has been implicated in both axon development and myelination by in vitro studies, we find no requirement for DOCK7 in neurobehavioral function in vivo. However, DOCK7 has non-redundant role(s) related to the distribution and function of dermal and follicular melanocytes.misty ͉ melanocyte ͉ coat color ͉ guanine nucleotide exchange factor ͉ rho GTPase

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“…It is interesting to note that RAC1 is involved in mTOR signaling and other disorders in this pathway also result in significant alterations in head size. 17,40,41 The variability of RAC1 phenotypes appear to be dependent on specific mutations, although the contribution of genetic background cannot be ruled out. In silico modeling, mouse fibroblasts spreading assays, and zebrafish experiments demonstrate that some RAC1 mutations (those encoding p.Cys18Tyr and p.Asn39Ser) genocopy a known dominant-negative mutant (p.Thr17Asn) and result in reduced neuronal proliferation, microcephaly, and cerebellar abnormalities in vivo.…”

mentioning

confidence: 99%

RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

Reijnders

Ansor

Kousi

et al. 2017

The American Journal of Human Genetics

123

140

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RAC1 is a widely studied Rho GTPase, a class of molecules that modulate numerous cellular functions essential for normal development. RAC1 is highly conserved across species and is under strict mutational constraint. We report seven individuals with distinct de novo missense RAC1 mutations and varying degrees of developmental delay, brain malformations, and additional phenotypes. Four individuals, each harboring one of c.53G>A (p.Cys18Tyr), c.116A>G (p.Asn39Ser), c.218C>T (p.Pro73Leu), and c.470G>A (p.Cys157Tyr) variants, were microcephalic, with head circumferences between À2.5 to À5 SD. In contrast, two individuals with c.151G>A (p.Val51Met) and c.151G>C (p.Val51Leu) alleles were macrocephalic with head circumferences of þ4.16 and þ4.5 SD. One individual harboring a c.190T>G (p.Tyr64Asp) allele had head circumference in the normal range. Collectively, we observed an extraordinary spread of $10 SD of head circumferences orchestrated by distinct mutations in the same gene. In silico modeling, mouse fibroblasts spreading assays, and in vivo overexpression assays using zebrafish as a surrogate model demonstrated that the p.Cys18Tyr and p.Asn39Ser RAC1 variants function as dominant-negative alleles and result in microcephaly, reduced neuronal proliferation, and cerebellar abnormalities in vivo. Conversely, the p.Tyr64Asp substitution is constitutively active. The remaining mutations are probably weakly dominant negative or their effects are context dependent. These findings highlight the importance of RAC1 in neuronal development. Along with TRIO and HACE1, a sub-category of rare developmental disorders is emerging with RAC1 as the central player. We show that ultra-rare disorders caused by private, non-recurrent missense mutations that result in varying phenotypes are challenging to dissect, but can be delineated through focused international collaboration.Developmental disorders (DDs) are etiologically extremely heterogeneous and affect 2%-5% of individuals.

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The mTOR pathway and its role in human genetic diseases

Cited by 160 publications

References 106 publications

Brain Tumor Signs and Symptoms: Analysis of Primary Health Care Records From the UKCCS

Brain Tumor Signs and Symptoms: Analysis of Primary Health Care Records From the UKCCS

Mice with mutations of Dock7 have generalized hypopigmentation and white-spotting but show normal neurological function

RAC1 Missense Mutations in Developmental Disorders with Diverse Phenotypes

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