Influence of mutation type and X chromosome inactivation on Rett syndrome phenotypes

TLDR

The study screened 78 Rett syndrome patients for MECP2 mutations and X‑chromosome inactivation patterns, and compared electrophysiology, CSF neurochemistry, and 13 clinical traits between missense and truncating mutation carriers. The authors identified 23 distinct MECP2 mutations in 76 % of sporadic and 29 % of familial patients, found that 91 % of classic cases had random X‑inactivation while nonrandom X‑inactivation was linked to milder phenotypes, and reported that truncating mutations were associated with respiratory dysfunction and lower CSF homovanillic acid, missense mutations with scoliosis, highlighting that mutation type and X‑inactivation patterns produce similar phenotypic spectra and support a partial loss‑of‑function mechanism.

Abstract

We screened 71 sporadic and 7 familial Rett syndrome (RTT) patients for MECP2 mutations by direct sequencing and determined the pattern of X chromosome inactivation (XCI) in 39 RTT patients. We identified 23 different disease-causing MECP2 mutations in 54 of 71 (76%) sporadic patients and in 2 of 7 (29%) familial cases. We compared electrophysiological findings, cerebrospinal fluid neurochemistry, and 13 clinical characteristics between patients carrying missense mutations and those carrying truncating mutations. Thirty-one of 34 patients (91%) with classic RTT had random XCI. Nonrandom XCI was associated with milder phenotypes, including a mitigated classic RTT caused by a rare early truncating mutation. Patients with truncating mutations have a higher incidence of awake respiratory dysfunction and lower levels of cerebrospinal fluid homovanillic acid. Scoliosis is more common in patients with missense mutations. These data indicate that different MECP2 mutations have similar phenotypic consequences, and random XCI plays an important role in producing the full phenotypic spectrum of classic RTT. The association of early truncating mutations with nonrandom XCI, along with the fact that chimeric mice lacking methyl-CpG-binding protein 2 (MeCP2) function die during embryogenesis, supports the notion that RTT is caused by partial loss of MeCP2 function.