MECP2 mutation spectrum and its clinical characteristics in a Chinese cohort

Abstract

The dysfunction of methyl‐CpG‐binding protein 2 (MeCP2) is associated with several neurological disorders, of which Rett syndrome (RTT) is the most prominent. This study focused on a Chinese patient cohort with MECP2 mutations, and analyzed the characteristics of these mutations and their clinical manifestations. In total, 666 patients were identified with 126 different MECP2 mutations, including 22 novel mutations. Over 80% of patients carried an MECP2 mutation on exon 4. Nonsense and missense mutations were the most commonly reported types. Missense mutations were mainly located on methyl‐CpG‐binding domain (MBD), and nonsense mutations predominantly occurred on transcription repression domain (TRD) and inter domain. The predilection site of large deletion was exon 3 and/or exon 4. Patients with p.R133C, p.R294*, p.R306C, and C‐terminal domain (CTD) deletions were less severely affected. Significant differences were found in ambulation ability, hand function, and language among different mutation groups. Three female patients with MECP2 mutations (1 with p.R306P and 2 with p.R309W) only presented with intellectual disability/developmental delay (ID/DD), and no obvious RTT symptoms were reported. Eight male individuals with MECP2 mutations were also identified in this study, including 2 diagnosed with typical RTT, 3 with atypical RTT and 3 with ID/DD.

MECP2 germline mosaicism plays an important part in the inheritance of Rett syndrome: a study of MECP2 germline mosaicism in males

“…Among fathers with RTT daughters, c.502C > T (p.R168*) was the most common MECP2 mosaicism in their sperm samples, followed by c.473C > T (p.T158M) and c.397C > T (p.R133C), which was basically consistent with their mutation rate in RTT patients according to our previous study [12]. The MECP2 mosaic mutations in RTT fathers may be influenced by the sample offset (their daughters' MECP2 mutations), so we recruited healthy adult males without RTT family history for further study.…”

“…MECP2 mutations accounted for about 95% of RTT patients, of which nearly 99% were de novo. In our previous study, ten MECP2 hotspot mutations were accounted for about 65% of RTT patients with MECP2 mutations [12]. As the incidence of RTT ranged from 1/15000 to 1/10000, the mutation rate of the ten MECP2 hotspots in females was about 4.1*10 -5 ~ 6.1*10 -5 (95%*99%*65%*1/15000 ~ 95%*99%*65% *1/10000).…”

MeCP2: The Genetic Driver of Rett Syndrome Epigenetics

“…It is also worth emphasizing that, until recently, no unequivocal RTT mutations have been reported within exon 2 (or indeed for any clinical entity). Very recently, however, there is a report of a NM_004992:c.7G > C; p.Ala3Pro Rett mutation in exon 2 (Wen et al, 2020). Given its rarity, it will be important to assess the molecular effects of this variant to confirm its true pathogenicity.…”

Genetics behind Cerebral Disease with Ocular Comorbidity: Finding Parallels between the Brain and Eye Molecular Pathology

“…A2V mutation affects co- and post-translational modifications, reducing N-acetylation and polyalanine, eventually causing higher proteasomal degradation [ 330 ]. A59P mutation affects the overall conformation of the protein backbone, which influences MBD expression [ 332 ]. There has been only one RTT patient with mutations in exon 2 ever reported [ 333 ], so more studies are needed to confirm the pathological mechanisms.…”