A novel hypomorphic MECP2 point mutation is associated with a neuropsychiatric phenotype

Abstract

The MECP2 gene on Xq28 encodes a transcriptional repressor, which binds to and modulates expression of active genes. Mutations in MECP2 cause classic or preserved speech variant Rett syndrome and intellectual disability in females and early demise or marked neurodevelopmental handicap in males. The consequences of a hypomorphic Mecp2 allele were recently investigated in a mouse model, which developed obesity, motor, social, learning, and behavioral deficits, predicting a human neurobehavioral syndrome. Here, we describe mutation analysis of a nondysmorphic female proband and her father who presented with primarily neuropsychiatric manifestations and obesity with relative sparing of intelligence, language, growth, and gross motor skills. We identified and characterized a novel missense mutation (c.454C>G; p.P152A) in the critical methyl-binding domain of MeCP2 that disrupts MeCP2 functional activity. We show that a gradient of impairment is present when the p.P152A mutation is compared with an allelic p.P152R mutation, which causes classic Rett syndrome and another Rett syndrome-causing mutation, such that protein-heterochromatin binding observed by immunofluorescence and immunoblotting is wild-type > P152A > P152R > T158 M, consistent with the severity of the observed phenotype. Our findings provide evidence for very mild phenotypes in humans associated with partial reduction of MeCP2 function arising from subtle variation in MECP2.

From Function to Phenotype: Impaired DNA Binding and Clustering Correlates with Clinical Severity in Males with Missense Mutations in MECP2

“…previously reported severely affected heterochromatin clustering in proline substitutions P101R, P101H and P152R. Similarly, Adegbola et al 18. reported disrupted MeCP2-heterochromatin binding for P152A, P152R and T158M.…”

“…P152R has been reported as a pathogenic variant only in females, showing classical, typical, and atypical Rett symptoms. In a single study, P152A was reported as a hypomorphic mutation in a male patient18. R106, R111, N126, R133, A140, P152, F157, T158 and R167 are conserved across all vertebrates (Fig.…”

Leptin resistance and obesity in mice with deletion of methyl-CpG-binding protein 2 (MeCP2) in hypothalamic pro-opiomelanocortin (POMC) neurons

“…However, most of these mouse models have altered MeCP2 in all or most of the CNS, making it difficult to delineate the specific role of MeCP2 in different neurons. Overweight or obesity is a common phenotype in mouse models with deletion of MeCP2 in postmitotic neurons, in postnatal CNS and in Sim1-expressing neurons [22,25,26], as well as in some patients with atypical RTT [37][38][39][40]. A plausible mechanism for the overweight or obesity phenotype may be the reduced levels of brain-derived neuropeptide (BDNF), an established regulator of energy balance [41] and target of MeCP2 regulation [42].…”

MECP2 disorders: from the clinic to mice and back

“…Secondly, in the rare cases of familial transmission, mothers with favorably skewed XCI patterns can transmit a mutant allele to viable hemizygous male offspring, but these males typically die in infancy if they inherit total loss-of-function alleles (13,19). Males with more mild mutations survive, exhibiting varying degrees of intellectual disability and, frequently, neuropsychiatric symptoms, such as bipolar disorder (20), schizophrenia (21), and attention deficit/hyperactivity disorder (ADHD) (22,23). Importantly, these male patients helped broaden the phenotypic spectrum due to MECP2 mutations.…”