The behavioural phenotype of Potocki-Lupski syndrome: a cross-syndrome comparison

RAI1 Overexpression Promotes Altered Circadian Gene Expression and Dyssomnia in Potocki–Lupski Syndrome

How much is too much? Phenotypic consequences of Rai1 overexpression in mice

Correct developmental expression level of Rai1 in forebrain neurons is required for control of body weight, activity levels and learning and memory

rAAV-CRISPRa therapy corrects Rai1 haploinsufficiency and rescues selective disease features in Smith-Magenis syndrome mice

Molecular and Neural Functions of Rai1, the Causal Gene for Smith-Magenis Syndrome

Increased expression of retinoic acid-induced gene 1 in the dorsolateral prefrontal cortex in schizophrenia, bipolar disorder, and major depression

Developing gene therapies to treat rare and ultra-rare neuromuscular disorders requires a sound understanding of the anatomy of genes and the various methods by which genetic mutations can be targeted. From our antisense oligonucleotide therapeutic for SCA3 in collaboration with Leiden University Medical Center to our gene replacement strategy for ADSSL1 gene-related myopathy with Boston Children’s Hospital, Cure Rare Disease is employing a variety of techniques to treat genetic diseases.

Potocki-Lupski syndrome (PTLS) and Smith-Magenis syndrome (SMS) are related genomic disorders, as duplication 17p11.2 (associated with PTLS) is the reciprocal recombination product of the SMS microdeletion. While SMS has a relatively well-delineated behavioural phenotype, the behavioural profile in PTLS is less well defined, despite purported associations with autism spectrum disorder (ASD) and the suggestion that some behaviours may be diametric to those seen in SMS.

Potocki–Lupski Syndrome (PTLS, MIM 610883), or duplication of chromosome 17p11.2, is a clinically recognizable condition characterized by infantile hypotonia, failure to thrive, developmental delay, intellectual disability, and congenital anomalies. Short stature, classified as greater than two standard deviations below the mean, has not previously been considered a major feature of PTLS. Retrospective chart review on a cohort of 37 individuals with PTLS was performed to investigate the etiology of short stature.

RAI1 is among the top 130 genes strongly associ- ated with idiopathic autism (Trost et al., 2022). This clinical evidence suggests that proper RAI1 levels are essential for brain development and function.

TCF20 is paralogous to RAI114, the causative gene in Potocki–Lupski syndrome (duplication of 17p11.2), which is associated with autism spectrum disorder (ASD) in ~90% of cases16,17; and Smith–Magenis syndrome (deletion of 17p11.2), characterized by severe intellectual disability and neurobehavioural problems, including ASD

TGT-001 corrects genes within the body directly, using the CRISPR gene-editing tool to regulate the expression of PMP22 to normal levels. This treatment is designed to treat CMT1A, which is caused by a duplication of the PMP22 gene.

Herein, we describe three patients with PTLS who were found-in the course of routine clinical care-to have a type 1 Arnold-Chiari malformation (CM-1)

Correct developmental expression level of Rai1 in forebrain neurons is required for control of body weight, activity levels and learning and memory

Definition of a critical genetic interval related to kidney abnormalities in Potocki-Lupski syndrome

Retinoic Acid Induced 1, RAI1: A Dosage Sensitive Gene Related to Neurobehavioral Alterations Including Autistic Behavior

insights from Smith-Magenis and Potocki-Lupski syndrome mouse models

An example with the smith-magenis and the potocki-lupski syndromes

We have generated a PTLS mouse model, Dp(11)17/+, that recapitulates some of the physical and neurobehavioral phenotypes present in patients.

We previously generated a mouse model for dup(17)(p11.2p11.2), Dp(11)17/+, that recapitulated most of the phenotypes observed in human patients. We have now analyzed compound heterozygous mice carrying a duplication [Dp(11)17] in one chromosome

For Smith-Magenis syndrome and dup(17)(p11.2p11.2)

Modeling del(17)(p11.2p11.2) and dup(17)(p11.2p11.2) contiguous gene syndromes by chromosome engineering in mice: phenotypic consequences of gene dosage imbalance

We have now analyzed compound heterozygous mice carrying a duplication [Dp(11)17

Evidence for genetic regulation of mRNA expression of the dosage-sensitive gene retinoic acid induced-1 (RAI1) in human brain

Retinoic Acid Induced 1, RAI1: A Dosage Sensitive Gene Related to Neurobehavioral Alterations Including Autistic Behavior

The work presented here represents the characterization of the human RAI1 gene. Our results show that this gene is very similar to its mouse ortholog both in DNA and protein sequences and in expression patterns