CapZyme-Seq Comprehensively Defines Promoter-Sequence Determinants for RNA 5' Capping with NAD.

Nucleoside-containing metabolites such as NAD+ can be incorporated as 5' caps on RNA by serving as non-canonical initiating nucleotides (NCINs) for transcription initiation by RNA polymerase (RNAP). Here, we report CapZyme-seq, a high-throughput-sequencing method that employs NCIN-decapping enzymes NudC and Rai1 to detect and quantify NCIN-capped RNA. By combining CapZyme-seq with multiplexed transcriptomics, we determine efficiencies of NAD+ capping by Escherichia coli RNAP for ∼16,000 promoter sequences. The results define preferred transcription start site (TSS) positions for NAD+ capping and define a consensus promoter sequence for NAD+ capping: HRRASWW (TSS underlined). By applying CapZyme-seq to E. coli total cellular RNA, we establish that sequence determinants for NCIN capping in vivo match the NAD+-capping consensus defined in vitro, and we identify and quantify NCIN-capped small RNAs (sRNAs). Our findings define the promoter-sequence determinants for NCIN capping with NAD+ and provide a general method for analysis of NCIN capping in vitro and in vivo.

CRISPR-based genome editing of a diurnal rodent, Nile grass rat (Arvicanthis niloticus).

BACKGROUND: Diurnal and nocturnal mammals have evolved distinct pathways to optimize survival for their chronotype-specific lifestyles. Conventional rodent models, being nocturnal, may not sufficiently recapitulate the biology of diurnal humans in health and disease. Although diurnal rodents are potentially advantageous for translational research, until recently, they have not been genetically tractable. The present study aims to address this major limitation by developing experimental procedures necessary for genome editing in a well-established diurnal rodent model, the Nile grass rat (Arvicanthis niloticus). RESULTS: A superovulation protocol was established, which yielded nearly 30 eggs per female grass rat. Fertilized eggs were cultured in a modified rat 1-cell embryo culture medium (mR1ECM), in which grass rat embryos developed from the 1-cell stage into blastocysts. A CRISPR-based approach was then used for gene editing in vivo and in vitro, targeting Retinoic acid-induced 1 (Rai1), the causal gene for Smith-Magenis Syndrome, a neurodevelopmental disorder. The CRISPR reagents were delivered in vivo by electroporation using an improved Genome-editing via Oviductal Nucleic Acids Delivery (i-GONAD) method. The in vivo approach produced several edited founder grass rats with Rai1 null mutations, which showed stable transmission of the targeted allele to the next generation. CRISPR reagents were also microinjected into 2-cell embryos in vitro. Large deletion of the Rai1 gene was confirmed in 70% of the embryos injected, demonstrating high-efficiency genome editing in vitro. CONCLUSION: We have established a set of methods that enabled the first successful CRISPR-based genome editing in Nile grass rats. The methods developed will guide future genome editing of this and other diurnal rodent species, which will promote greater utility of these models in basic and translational research.

Pentanucleotide Repeat Insertions in RAI1 Cause Benign Adult Familial Myoclonic Epilepsy Type 8.

BACKGROUND: Benign adult familial myoclonic epilepsy (BAFME) is an autosomal dominant disorder characterized by cortical tremors and seizures. Six types of BAFME, all caused by pentanucleotide repeat expansions in different genes, have been reported. However, several other BAFME cases remain with no molecular diagnosis. OBJECTIVES: We aim to characterize clinical features and identify the mutation causing BAFME in a large Malian family with 10 affected members. METHODS: Long-read whole genome sequencing, repeat-primed polymerase chain reaction and RNA studies were performed. RESULTS: We identified TTTTA repeat expansions and TTTCA repeat insertions in intron 4 of the RAI1 gene that co-segregated with disease status in this family. TTTCA repeats were absent in 200 Malian controls. In the affected individuals, we found a read with only nine TTTCA repeat units and somatic instability. The RAI1 repeat expansions cause the only BAFME type in which the disease-causing repeats are in a gene associated with a monogenic disorder in the haploinsufficiency state (ie, Smith-Magenis syndrome [SMS]). Nevertheless, none of the Malian patients exhibited symptoms related to SMS. Moreover, leukocyte RNA levels of RAI1 in six Malian BAFME patients were no different from controls. CONCLUSIONS: These findings establish a new type of BAFME, BAFME8, in an African family and suggest that haploinsufficiency is unlikely to be the main pathomechanism of BAFME. © 2023 International Parkinson and Movement Disorder Society. This article has been contributed to by U.S. Government employees and their work is in the public domain in the USA.

Case Report: A Case of a Patient with Smith-Magenis Syndrome and Early-Onset Parkinson's Disease.

Smith-Magenis Syndrome (SMS) is a rare genetic disorder, characterized by intellectual disability (ID), behavioral impairments, and sleep disturbances, as well as multiple organ anomalies in some affected individuals. The syndrome is caused by a deletion in the chromosome band around 17p11.2, including the Retinoic Acid Induced 1 (RAI1) gene, a multifaceted transcriptional regulator that modulates the expression of genes involved in cellular proliferation and neurodevelopment. This gene has a positive role in regulating BDNF and, importantly, affects several cell mechanisms and pathways such as the nigro-striatal pathway, which is crucial for motor function. Parkinson's disease (PD) is one of the most common neurodegenerative diseases in older populations. It is characterized by various physical symptoms including tremors, loss of balance, bradykinesia, and a stooping posture. We present a case study of a patient diagnosed with both SMS and early-onset PD (at the age of 49). The association between both conditions is as yet ambiguous. Genome-wide association studies (GWAS) implicate an association between the RAI1 gene and PD. Similarly, the co-existence of both SMS and PD in the patient suggests a possible association between RAI1 copy number variations (CNVs) and PD, further indicating that RAI1 has strong implications for PD pathogenesis. Our results suggest that RAI1 CNVs and the pathophysiology of PD may be related, underscoring the need for further research in this field. Therefore, caregivers of SMS patients should pay careful attention to the possibility of their patients developing EOPD and should consider starting treatment for PD as soon as the first symptoms appear.

Psychiatric and neurological manifestations in adults with Smith-Magenis syndrome: A scoping review.

Smith-Magenis syndrome (SMS) is a neurodevelopmental disorder caused by a 17p11.2 deletion or a pathogenic variant of the RAI1 gene, which lies within the 17p11.2 region. Various psychiatric and neurological disorders have been reported in SMS, with most literature focusing on children and adolescents. To provide an overview of the current knowledge on this topic in adults with SMS, we performed a comprehensive scoping review of the relevant literature. Our findings suggest that many manifestations that are common in childhood persist into adulthood. Neuropsychiatric manifestations in adults with SMS include intellectual disability, autism spectrum- and attention deficit hyperactivity disorder-related features, self-injurious and physical aggressive behaviors, sleep-wake disorders, and seizures. Findings of this review may facilitate optimization of management strategies in adults with SMS, and may guide future studies exploring late-onset psychiatric and neurological comorbidities in SMS.

Low-grade parental gonosomal mosaicism in CHD2 siblings with Smith-Magenis-like syndrome.

Loss-of-function CHD2 (chromodomain helicase DNA-binding protein 2) mutations are associated with a spectrum of neurodevelopmental disorders often including early-onset generalized seizures, photosensitivity, and epileptic encephalopathies. Patients show psychomotor delay/intellectual disability (ID), autistic features, and behavior disorders, such as aggression and impulsivity. Most reported cases are sporadic with description of germline mosaicism only in two families. We detect the first case of parental gonosomal CHD2 mosaicism disclosed by two brothers showing mild ID, born to healthy parents. The eldest brother has a history of drug-controlled generalized tonic-clonic seizures and displays sleep disorder and aggressive behavior suggestive of Smith-Magenis syndrome (SMS). Analysis of brothers' DNAs by next-generation sequencing (NGS) custom gene panel for pediatric epilepsy and/or ID disclosed in both the same pathogenic CHD2 variant. Additional NGS experiment on genomic DNA from parents' peripheral blood and from buccal swab raised the suspicion of low-grade gonosomal mosaicism in the unaffected mother subsequently confirmed by digital polymerase chain reaction (dPCR). This report underlines as worthwhile CHD2 screening in individuals presenting ID/developmental delay, with/without epilepsy, and behavior and sleep disorders suggestive of SMS. Detecting a CHD2 variant should prime testing probands' parents by NGS coupled to dPCR on different tissues to exclude/confirm gonosomal mosaicism and define the recurrence risk.

Recent insights into noncanonical 5' capping and decapping of RNA.

The 5' N7-methylguanosine cap is a critical modification for mRNAs and many other RNAs in eukaryotic cells. Recent studies have uncovered an RNA 5' capping quality surveillance mechanism, with DXO/Rai1 decapping enzymes removing incomplete caps and enabling the degradation of the RNAs, in a process we also refer to as "no-cap decay." It has also been discovered recently that RNAs in eukaryotes, bacteria, and archaea can have noncanonical caps (NCCs), which are mostly derived from metabolites and cofactors such as NAD, FAD, dephospho-CoA, UDP-glucose, UDP-N-acetylglucosamine, and dinucleotide polyphosphates. These NCCs can affect RNA stability, mitochondrial functions, and possibly mRNA translation. The DXO/Rai1 enzymes and selected Nudix (nucleotide diphosphate linked to X) hydrolases have been shown to remove NCCs from RNAs through their deNADding, deFADding, deCoAping, and related activities, permitting the degradation of the RNAs. In this review, we summarize the recent discoveries made in this exciting new area of RNA biology.

Smith Magenis syndrome: First case of congenital heart defect in a patient with Rai1 mutation.

Smith Magenis syndrome (SMS) is a rare neurobehavioral disorder caused by 17p11.2 microdeletion encompassing Retinoic Acid-Induced 1 (RAI1) gene (90% of cases) or by RAI1 point mutation (10% of cases). The neuropsychological phenotype of individuals with 17p11.2 deletion and in those with RAI1 variants mostly overlaps. However, cardiac defects have been described only in patients with a deletion so far. Here, we present the first case of a patient affected by SMS caused by RAI1 variant in whom a severe congenital pulmonary valve stenosis was diagnosed at birth, requiring trans catheter dilatation in the first month of life. This case expands the phenotypic spectrum associated with RAI1 variants in SMS, describing a previously unreported association with a congenital heart disease.

Importance of OsRac1 and RAI1 in signalling of nucleotide-binding site leucine-rich repeat protein-mediated resistance to rice blast disease.

Plants depend on Resistance (R) genes, most of which encode nucleotide-binding site leucine-rich repeat (NLR) proteins, for pathogen race-specific disease resistance. However, only a few immediate downstream targets of R proteins have been characterized, and the signalling pathways for R-protein-induced immunity are largely unknown. In rice (Oryza sativa), NLR proteins serve as important immune receptors in the response to rice blast disease caused by the fungus Magnaporthe oryzae. We used site-directed mutagenesis to create an autoactive form of the NLR protein PID3 that confers blast resistance and used transgenic rice to test the resulting immunity and gene expression changes. We identified OsRac1, a known GTPase, as a signalling molecule in PID3-mediated blast resistance, implicating OsRac1 as a possible common factor downstream of rice NLR proteins. We also identified RAI1, a transcriptional activator, as a PID3 interactor required for PID3-mediated blast resistance and showed that RAI1 expression is induced by PID3 via a process mediated by OsRac1. This study describes a new signalling pathway for NLR protein-mediated blast resistance and shows that OsRac1 and RAI1 act together to play a critical role in this process.

Twenty-four-hour motor activity and body temperature patterns suggest altered central circadian timekeeping in Smith-Magenis syndrome, a neurodevelopmental disorder.

Smith-Magenis syndrome (SMS) is a contiguous gene syndrome linked to interstitial microdeletion, or mutation of RAI1, within chromosome 17p11.2. Key behavioral features of SMS include intellectual disability, sleep-disturbances, maladaptive, aggressive and self-injurious behaviors, hyperactivity, and sudden changes in mood. A distinguishing feature of this syndrome is an inverted pattern of melatonin characterized by elevated daytime and low nighttime melatonin levels. As the central circadian clock controls the 24-hr rhythm of melatonin, we hypothesized that the clock itself may contribute to the disrupted pattern of melatonin and sleep. In this report, 24-hr patterns of body temperature, a surrogate marker of clock-timing, and continuous wrist activity were collected to examine the links between body temperature, sleep behavior, and the circadian clock. In addition, age-dependent changes in sleep behavior were explored. Actigraphy-estimated sleep time for SMS was 1 hr less than expected across all ages studied. The timing of the 24-hr body temperature (Tb-24) rhythm was phase advanced, but not inverted. Compared to sibling (SIB) controls, the SMS group had less total night sleep, lower sleep efficiency, earlier sleep onset, earlier final awake times, increased waking after sleep onset (WASO), and increased daytime nap duration. The timing of wake onset varied with age, providing evidence of ongoing developmental sleep changes from childhood through adolescence. Clarification of the circadian and developmental factors that contribute to the disrupted and variable sleep patterns in this syndrome will be helpful in identifying more effective individualized treatments.

Transcriptome Sequencing Reveals Potential Mechanisms of the Maternal Effect on Egg Diapause Induction of Locusta migratoria.

Photoperiod is one of the most important maternal factors with an impact on the offspring diapause induction of Locusta migratoria. Previous studies have shown that forkhead box protein O (FOXO) plays an important role in regulating insect diapause, but how photoperiod stimulates maternal migratory locusts to regulate the next generation of egg diapause through the FOXO signaling pathway still needs to be addressed. In this study, the transcriptomes of ovaries and fat bodies of adult locusts under a long and short photoperiod were obtained. Among the total of 137 differentially expressed genes (DEGs) in both ovaries and fat bodies, 71 DEGs involved in FOXO signaling pathways might be closely related to diapause induction. 24 key DEGs were selected and their expression profiles were confirmed to be consistent with the transcriptome results using qRT-PCR. RNA interference was then performed to verify the function of retinoic acid induced protein gene (rai1) and foxo. Egg diapause rates were significantly increased by RNAi maternal locusts rai1 gene under short photoperiods. However, the egg diapause rates were significantly decreased by knock down of the foxo gene in the maternal locusts under a short photoperiod. In addition, reactive oxygen species (ROS) and superoxide dismutase (SOD) activities were promoted by RNAi rai1. We identified the candidate genes related to the FOXO pathway, and verified the diapause regulation function of rai1 and foxo under a short photoperiod only. In the future, the researchers can work in the area to explore other factors and genes that can promote diapause induction under a long photoperiod.

Smith-Magenis Syndrome: Molecular Basis of a Genetic-Driven Melatonin Circadian Secretion Disorder.

Smith-Magenis syndrome (SMS), linked to Retinoic Acid Induced (RAI1) haploinsufficiency, is a unique model of the inversion of circadian melatonin secretion. In this regard, this model is a formidable approach to better understand circadian melatonin secretion cycle disorders and the role of the RAI1 gene in this cycle. Sleep-wake cycle disorders in SMS include sleep maintenance disorders with a phase advance and intense sleepiness around noon. These disorders have been linked to a general disturbance of sleep-wake rhythm and coexist with inverted secretion of melatonin. The exact mechanism underlying the inversion of circadian melatonin secretion in SMS has rarely been discussed. We suggest three hypotheses that could account for the inversion of circadian melatonin secretion and discuss them. First, inversion of the circadian melatonin secretion rhythm could be linked to alterations in light signal transduction. Second, this inversion could imply global misalignment of the circadian system. Third, the inversion is not linked to a global circadian clock shift but rather to a specific impairment in the melatonin secretion pathway between the suprachiasmatic nuclei (SCN) and pinealocytes. The development of diurnal SMS animal models that produce melatonin appears to be an indispensable step to further understand the molecular basis of the circadian melatonin secretion rhythm.

First evidence of Smith-Magenis syndrome in mother and daughter due to a novel RAI mutation.

Smith-Magenis syndrome (SMS) is a complex genetic disorder caused by interstitial 17p11.2 deletions encompassing multiple genes, including the retinoic acid induced 1 gene-RAI1-or mutations in RAI1 itself. The clinical spectrum includes developmental delay, cognitive impairment, and behavioral abnormalities, with distinctive physical features that become more evident with age. No patients have been reported to have had offspring. We here describe a girl with developmental delay, mainly compromising the speech area, and her mother with mild intellectual disabilities and minor dysmorphic features. Both had sleep disturbance and attention deficit disorder, but no other atypical behaviors have been reported. In both, CGH-array analysis detected a 15q13.3 interstitial duplication, encompassing CHRNA7. However, the same duplication has been observed in several, apparently healthy, maternal relatives. We, thus, performed a whole exome sequencing analysis, which detected a frameshift mutation in RAI1, de novo in the mother, and transmitted to her daughter. No other family members carried this mutation. This is the first report of an SMS patient having offspring. Our experience confirms the importance of searching for alternative causative genetic mechanisms in case of confounding/inconclusive findings such as a CGH-array result of uncertain significance. © 2016 Wiley Periodicals, Inc.

Delayed diagnosis in a house of correction: Smith-Magenis syndrome due to a de novo nonsense RAI1 variant.

We report a 25-year-old female confirmed to have Smith-Magenis syndrome (SMS) due to a de novo RAI1 variant. Her past history is significant for developmental and intellectual delay, early and escalating maladaptive behaviors, and features consistent with significant sleep disturbance, the etiology of which was not confirmed for over two decades. The diagnosis of SMS was initially suspected in 1998 (at age 12 years), but that was 5 years before the initial report of RAI1 variants as causative of the SMS phenotype; cytogenetic fluorescence in situ hybridization studies failed to confirm an interstitial deletion of 17p11.2. Re-evaluation for suspected SMS was pursued with RAI1 sequencing analysis in response to urgent parental concerns of escalating behaviors and aggression with subsequent incarceration of the subject for assault of a health professional. Genetic analysis revealed a de novo RAI1 (NM_030665.3) nonsense variant, c.5536C>T; p.Q1846X. This case illustrates the importance of confirming the SMS diagnosis, which is associated with cognitive and functional impairment, as well as significant psychiatric co-morbidities and behavioral problems. The diagnosis was particularly relevant to the legal discussion and determination of her competence to stand trial. As other similar cases may exist, this report will help to increase awareness of the possibility of a very late diagnosis of SMS, with the need for re-evaluation of individuals suspected to have SMS who were initially evaluated prior to the identification of the RAI1 gene. © 2016 Wiley Periodicals, Inc.

Inherited dup(17)(p11.2p11.2): expanding the phenotype of the Potocki-Lupski syndrome.

Potocki-Lupski syndrome (PTLS, OMIM: 610883) is a microduplication syndrome characterized by infantile hypotonia, failure to thrive, cardiovascular malformations, developmental delay, intellectual disability, and behavior abnormalities, the latter of which can include autism spectrum disorder. The majority of individuals with PTLS harbor a de novo microduplication of chromosome 17p11.2 reciprocal to the common recurrent 3.6 Mb microdeletion in the Smith-Magenis syndrome critical region. Here, we report on the transmission of the PTLS duplication across two generations in two separate families. Individuals in these families presented initially with developmental delay, behavior problems, and intellectual disability. We provide a detailed review of the clinical and developmental phenotype of inherited PTLS in both families. This represents the second report (second and third families) of PTLS in a parent-child pair and exemplifies the under-diagnosis of this and likely other genetic conditions in adults with intellectual disability and/or psychiatric disorders.

Overlapping hearing and communication profiles for the deletion and the RAI1 variant form of Smith-Magenis Syndrome (SMS).

Smith-Magenis syndrome (SMS), a rare, genetically linked complex developmental disorder is associated with hearing loss and delays in speech-language development. Approximately 70 % of those with SMS have a genetic deletion within chromosome 17p11.2 and 10 % have a single gene mutation in the same area, known as the RAI1 variant form of SMS. Previous studies presented preliminary comparisons of the phenotype of those with deletion versus the mutation form of SMS, but none focused on hearing, speech-language, and communication profiles. The current study examined patient registry data and compared two groups of individuals with SMS to determine if genetic differences influence the communication phenotype and to determine the importance of the RAI1 gene in hearing, speech, and language abilities in children. Speech-language and hearing data from the international SMS Patient Registry for 33 subjects with SMS were analyzed: 23 with a genetic deletion (SMS (del)) and 10 with an RAI1 mutation (SMS (RAI1)). Hearing status, otopathology findings, early speech-language milestones, mode of communication, intelligibility, vocal quality, language abilities, and literacy skills were analyzed. There were small differences between the groups for hearing status, otopathological findings, mode of communication, voice quality, intelligibility, speech-language abilities, and literacy. Overlap in the speech-language phenotype between groups confirms previous hypotheses that suggest haploinsufficiency of the RAI1 gene is responsible for the SMS phenotype and that the RAI1 gene is critical for speech-language development. Future studies should include direct testing of receptive and expressive language abilities, including analyses of language samples, with larger groups of individuals to replicate and extend the current findings.

Comparative analyses of the Smith-Magenis syndrome protein RAI1 in mice and common marmoset monkeys.

Retinoic acid-induced 1 (RAI1) encodes a transcriptional regulator critical for brain development and function. RAI1 haploinsufficiency in humans causes a syndromic autism spectrum disorder known as Smith-Magenis syndrome (SMS). The neuroanatomical distribution of RAI1 has not been quantitatively analyzed during the development of the prefrontal cortex, a brain region critical for cognitive function and social behaviors and commonly implicated in autism spectrum disorders, including SMS. Here, we performed comparative analyses to uncover the evolutionarily convergent and divergent expression profiles of RAI1 in major cell types during prefrontal cortex maturation in common marmoset monkeys (Callithrix jacchus) and mice (Mus musculus). We found that while RAI1 in both species is enriched in neurons, the percentage of excitatory neurons that express RAI1 is higher in newborn mice than in newborn marmosets. By contrast, RAI1 shows similar neural distribution in adult marmosets and adult mice. In marmosets, RAI1 is expressed in several primate-specific cell types, including intralaminar astrocytes and MEIS2-expressing prefrontal GABAergic neurons. At the molecular level, we discovered that RAI1 forms a protein complex with transcription factor 20 (TCF20), PHD finger protein 14 (PHF14), and high mobility group 20A (HMG20A) in the marmoset brain. In vitro assays in human cells revealed that TCF20 regulates RAI1 protein abundance. This work demonstrates that RAI1 expression and protein interactions are largely conserved but with some unique expression in primate-specific cells. The results also suggest that altered RAI1 abundance could contribute to disease features in disorders caused by TCF20 dosage imbalance.

Allele-Specific Regulation of the Candidate Autism Liability Gene RAI1 by the Enhancer Variant rs4925102 (C/G).

Retinoic acid-induced 1 (RAI1) is a dosage-sensitive gene that causes autistic phenotypes when deleted or duplicated. Observations from clinical cases and animal models also suggest that changes of RAI1 expression levels contribute to autism. Previously, we used a bioinformatic approach to identify several single nucleotide polymorphisms (SNPs) located within the 5'-region of RAI1 that correlate with RAI1 mRNA expression in the human brain. In particular, the SNP rs4925102 was identified as a candidate cis-acting regulatory variant, the genotype of which may affect the binding of transcription factors that influence RAI1 mRNA expression. In this study, we provide experimental evidence based on reporter gene, chromatin immunoprecipitation (ChIP), and chromatin conformation capture (3C) assays that rs4925102 regulates RAI1 mRNA expression in an allele-specific manner in human cell lines, including the neuroblastoma-derived cell line SH-SY5Y. We also describe a statistically significant association between rs4925102 genotype and autism spectrum disorder (ASD) diagnosis in a case-control study and near-statistically significant association in an Autism Genome Project (AGP) transmission disequilibrium (TDT) study using Caucasian subjects.

A de novo mutation (p.S1419F) of Retinoic acid induced 1 is responsible for a patient with Smith-Magenis syndrome exhibiting schizophrenia.

Smith-Magenis syndrome (SMS, OMIM# 182290) is a rare congenital disorder which characterized by multiple abnormalities involving in craniofacial, skeletal, otorhinolaryngolocial, neurological, behavioral and others. 17p11.2 microdeletion and RAI1 mutations have been proven to be genetic lesions of this disease. However, the relationship between RAI1 variants and different phenotypes is still unclear. The discoveries of more RAI1 mutations in patients with different phenotypes will help to elucidate the pathogenesis of the RAI1 gene. Here, we describe a young patient with schizophrenia and headache as the main clinical presentation, with SMS-like features including depression, sleep disturbance and pain-free status. Whole exome sequencing and Sanger sequencing suggested that a de novo mutation (NM_030665.3: c.4256C > T/p.S1419F) of RAI1 may be the genetic lesion of the patient. The bioinformatic program predicted that the new mutation (p.S1419F), located in an evolutionarily conserved site of RAI1, was deleterious. Further, western blot analysis suggested that the novel mutation may decrease the protein levels of RAI1 in the patient. Hence, we reported a novel mutation of RAI1 in a patient with SMS, schizophrenia and headache. Our study may expand the spectrum of RAI1 mutations which may further contribute to the mechanisms underlying SMS, schizophrenia and headache.

A case of Smith-Magenis syndrome with skin manifestations caused by a novel locus mutation in the RAI1 gene.

We report the clinical features and genetic testing of a child with Smith-Magenis syndrome (SMS) to improve the understanding of this disease. The clinical data and molecular genetic test results of a child with SMS caused by a novel mutation in the retinoic acid-induced-1 (RAI1) gene were reviewed. A female patient aged 12 years and 9 months presented to the clinic because her mental and motor development was lagging behind that of her peers. The child had learning difficulties, poor motor coordination, temper tantrums, and self-injurious behaviors, such as skin scratching. She had a peculiar facial appearance, dry skin with scattered eczema, low hairline, wide forehead, flat face, collapsed nasal bridge, turned out upper lip, and deep palmar lines on the right hand through the palm. Wechsler's IQ test score was 48. Her electroencephalogram was normal. The diagnosis of SMS was confirmed by a heterozygous mutation in exon 3 of the RAI1 gene on chromosome chr-1717696650 at locus c.388C>T (P.Q130X). In addition, this patient had severe eczema on the skin. The RAI1 mutation c.388C>T (P.Q130X) is a newly reported variant that will help in the clinical identification of SMS and the precise localization of more phenotypically related genes.