RettBASE: The IRSA MECP2 variation database—a new mutation database in evolution

Christodoulou, John; Grimm, Andrew; Maher, Tony; Bennetts, Bruce

doi:10.1002/humu.10194

Cited by 152 publications

(132 citation statements)

References 29 publications

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“…The exact coincidence between the four residues crucial to the MeCP2-TBL1/TBLR1 interaction and the four residues mutated in RTT makes it highly likely that TBL1 and TBLR1 are essential partners of MeCP2. It is notable that over 200 independent cases of the R306C mutation have been reported, whereas mutation of P302 to R, L, or A has been seen 23 times (32). Missense mutations at K305 and K304 are rarer, having been reported only four and two times, respectively.…”

Section: Discussionmentioning

confidence: 99%

“…Strikingly, missense substitutions at each of these four residues (P302, K304, K305, and R306) are reported in multiple independent cases of RTT. On the other hand, pathological substitutions at other NID residues are not reported in a database with over 1,000 RTT mutations (32). The cocrystal structure explains in molecular detail why known RTT mutations in the NID likely prevent association with the NCoR/SMRT corepressor complex.…”

Section: Mecp2mentioning

confidence: 92%

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Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

Kruusvee

Lyst

Taylor

et al. 2017

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

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Rett syndrome (RTT) is an X-linked neurological disorder caused by mutations in the methyl-CpG-binding protein 2 (MeCP2) gene. The majority of RTT missense mutations disrupt the interaction of the MeCP2 with DNA or the nuclear receptor corepressor (NCoR)/silencing mediator of retinoic acid and thyroid receptors (SMRT) corepressor complex. Here, we show that the "NCoR/SMRT interaction domain" (NID) of MeCP2 directly contacts transducin beta-like 1 (TBL1) and TBL1 related (TBLR1), two paralogs that are core components of NCoR/SMRT. We determine the cocrystal structure of the MeCP2 NID in complex with the WD40 domain of TBLR1 and confirm by in vitro and ex vivo assays that mutation of interacting residues of TBLR1 and TBL1 disrupts binding to MeCP2. Strikingly, the four MeCP2-NID residues mutated in RTT are those residues that make the most extensive contacts with TBLR1. Moreover, missense mutations in the gene for TBLR1 that are associated with intellectual disability also prevent MeCP2 binding. Our study therefore reveals the molecular basis of an interaction that is crucial for optimal brain function.T he methyl-CpG-binding protein 2 (MeCP2) is a chromatinassociated factor that is highly expressed in the brain (1, 2). Loss-of-function mutations in MeCP2 lead to the severe pediatric neurological disorder, Rett syndrome (RTT) (3), which affects around one in 10,000 girls. In addition, extra copies of the gene cause MeCP2 duplication syndrome (4, 5), a distinct intellectual disability disorder that predominantly affects males (6). The importance of MeCP2 for brain function has prompted investigation of its molecular function. The protein was identified because of its ability to bind DNA via its methyl-CpG-binding domain (MBD) (1, 7) and many residues mutated in RTT disrupt this interaction (8-11). In addition to DNA, numerous protein partners of MeCP2 have been reported (11). Of these protein partners, only the interactions with the nuclear receptor corepressor (NCoR) and its close relative silencing mediator of retinoic acid and thyroid receptors (SMRT) (12-14) are known to be disrupted by RTT missense mutations (13). Accordingly, Rett missense mutations outside the MBD are found clustered within the so-called "NCoR/SMRT interaction domain" (NID) (13) (Fig. 1A and Fig. S1A). One NID mutation, R306C, causes a severe RTT-like phenotype in mice (13,15,16). Moreover, mouse models of MeCP2 duplication syndrome suggest that both the MBD and the NID must be intact for this adverse molecular pathology to develop (16,17).These findings indicate that the NID mediates an essential function of MeCP2. This function may be recruitment of the NCoR/ SMRT corepressor complexes to chromatin. Alternatively, the NID may perform other essential roles, such as DNA binding, whose loss leads to RTT (16). In an attempt to distinguish among these possibilities, we investigated the molecular basis of the interaction between MeCP2 and NCoR/SMRT. The latter are ∼1.2-MDa multisubunit complexes that include NCoR1 (and/or SMRT), HDAC3, GPS2, and...

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Section: Discussionmentioning

confidence: 99%

Section: Mecp2mentioning

confidence: 92%

Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

Kruusvee

Lyst

Taylor

et al. 2017

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

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“…27,28 Mutations in MECP2 were first reported in 1999, 29 and subsequent screening of RTT patients has shown that almost 90 -95% of classical RTT have pathogenic mutations. 30 To date over 200 individual nucleotide changes which cause pathogenic mutations have been described (Figure 4, RettBASE; mecp2.chw.edu.au 31 and MeCP2.org.uk); however, the eight most commonly occurring missense and nonsense mutations account for almost 70% of all mutations, and small deletions associated with a deletion hotspot in the C-terminal region of the MeCP2 protein account for an additional 9% of pathogenic mutations. Mutations are found throughout the gene, and more recently large deletions (kilobases in size) that delete whole exons have also been identified in a proportion of patients who were previously considered to be mutation negative, and are more commonly found in individuals with classical (36%; 46 out of 128) than atypical (3%; seven out of 229) RTT cases.…”

Section: Mutations In Mecp2mentioning

confidence: 99%

Rett syndrome: new clinical and molecular insights

2006

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“…2 The first line of genetic testing involves mutation screening and sequencing of exons 3 and 4 for small sequence changes. 3 Over 200 MECP2 mutations have been identified 4 with some point mutations (p.R106W, p.R133C, p.R168X, p.R255X, p.R270X, p.R294X, p.R306C and p.T158M) occurring more commonly. Subsequent to sequencing, multiplex ligation-dependent probe amplification (MLPA) has also became available for the detection of deletions of one or more exons.…”

Section: Introductionmentioning

confidence: 99%

The phenotype associated with a large deletion on MECP2

et al. 2012

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Multiplex ligation-dependent Probe Amplification (MLPA) has become available for the detection of a large deletion on the MECP2 gene allowing genetic confirmation of previously unconfirmed cases of clinical Rett syndrome. This study describes the phenotype of those with a large deletion and compares with those with other pathogenic MECP2 mutations. Individuals were ascertained from the Australian Rett Syndrome and InterRett databases with data sourced from family and clinician questionnaires, and two case studies were constructed from the longitudinal Australian data. Regression and survival analysis were used to compare severity and age of onset of symptoms in those with and without a large deletion. Data were available for 974 individuals including 51 with a large deletion and ages ranged from 1 year 4 months to 49 years (median 9 years). Those with a large deletion were more severely affected than those with other mutation types. Specifically, individuals with large deletions were less likely to have learned to walk (OR 0.42, 95% CI: 0.22-0.79, P¼0.007) and to be currently walking (OR 0.53, 95% CI: 0.26-1.10, P¼0.089), and were at higher odds of being in the most severe category of gross motor function (OR 1.84, 95% CI: 0.98-3.48, P¼0.057) and epilepsy (OR 2.72, 95% CI: 1.38-5.37, P¼0.004). They also developed epilepsy, scoliosis, hand stereotypies and abnormal breathing patterns at an earlier age. We have described the disorder profile associated with a large deletion from the largest sample to date and have found that the phenotype is severe with motor skills particularly affected.

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RettBASE: The IRSA MECP2 variation database—a new mutation database in evolution

Cited by 152 publications

References 29 publications

Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

Structure of the MeCP2–TBLR1 complex reveals a molecular basis for Rett syndrome and related disorders

Rett syndrome: new clinical and molecular insights

The phenotype associated with a large deletion on MECP2

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