NIPA1 Gene Mutations Cause Autosomal Dominant Hereditary Spastic Paraplegia (SPG6)

Rainier, Shirley; Chai, Jing; Tokarz, Debra A; Nicholls, Robert D.; Fink, John K.

doi:10.1086/378817

Cited by 187 publications

(148 citation statements)

References 14 publications

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“…Similarly, these 3 genes have been implicated in central nervous system development and/or function. NIPA1 has been associated with spastic paraplegia, 17 whereas NIPA2 is conserved in vertebrates and widely expressed, including in the central nervous system. NIPA2 contains sequences with similarity to transmembrane domains, suggesting receptor or transporter function.…”

Section: Discussionmentioning

confidence: 99%

“…NIPA1 is expressed in mouse brain tissue but is not imprinted. In addition, NIPA1 is implicated in spastic paraplegia, 17 suggesting that it may be important for central nervous system development and/or function. Hence, we report gene-expression studies with the 4 genes located between BP1 and BP2 in those individuals with PWS with TI or TII deletions previously studied 14 and examined the relationship between messenger-RNA (mRNA) levels and behavioral-and intellectual-assessment scores.…”

Section: Introductionmentioning

confidence: 99%

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Expression of 4 Genes Between Chromosome 15 Breakpoints 1 and 2 and Behavioral Outcomes in Prader-Willi Syndrome

Bittel

Kibiryeva²,

Butler³

2006

Pediatrics

107

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Prader-Willi syndrome is a neurodevelopmental disorder that is characterized by infantile hypotonia, feeding difficulties, hypogonadism, mental deficiency, hyperphagia (leading to obesity in early childhood), learning problems, and behavioral difficulties. A paternal 15q11-q13 deletion is found in ~70% of patients with Prader-Willi syndrome, ~25% have uniparental maternal disomy 15, and the remaining 2% to 5% have imprinting defects. The proximal deletion breakpoint in the 15q11-q13 region occurs at 1 of 2 sites located within either of 2 large duplicons allowing for the identification of 2 deletion subgroups. The larger, type I (TI) deletion involves breakpoint 1, which is close to the centromere, whereas the smaller, type II (TII) deletion involves breakpoint 2, located ~500 kilobases distal to breakpoint 1. Breakpoint 3 is located at the distal end of the 15q11-q13 region and common to both typical deletion subgroups. Analyses of the genetic subtypes of Prader-Willi syndrome to date have primarily compared individuals with typical deletion and uniparental maternal disomy 15 without grouping the individuals with a deletion into TI or TII. Distinct differences have been reported between individuals with Prader-Willi syndrome resulting from deletion compared with uniparental maternal disomy 15 in physical, cognitive, and behavioral parameters. We previously presented the first assessment of clinical differences in individuals with Prader-Willi syndrome categorized as having type I or II deletions. Adaptive behavior, obsessive-compulsive behaviors, reading, math, and visual-motor integration assessments were generally poorer in individuals with Prader-Willi syndrome and the TI deletion compared with subjects with Prader-Willi syndrome with the TII deletion or uniparental maternal disomy 15. Four genes (NIPA1, NIPA2, CYFIP1, and GCP5) have been identified in the chromosomal region between breakpoints 1 and 2 and are implicated in compulsive behavior and lower intellectual ability observed in individuals with Prader-Willi syndrome with TI versus TII deletions. We quantified messenger-RNA levels of these 4 genes in actively growing lymphoblastoid cells derived from 8 subjects with Prader-Willi syndrome with the TI deletion (4 males, 4 females; mean: age 25.2 ± 8.9 years) and 9 with the TII deletion (3 males, 6 females; mean age: 19.5 ± 5.8 years). Messenger-RNA levels were correlated with validated psychological and behavioral scales administered by trained psychologists blinded to genotype status. Messenger RNA from NIPA1, NIPA2, CYFIP1, and GCP5 was reduced but detectable in the subjects with Prader-Willi syndrome with the TI deletion, supporting biallelic expression. For the most part, Address correspondence to Merlin G. Butler, MD, PhD, Children's Mercy Hospitals and Clinics, Section of Medical Genetics and Molecular Medicine, 2401 Gillham Rd, Kansas City, MO 64108. mgbutler@cmh.edu. The authors have indicated they have no financial relationships relevant to this article to disclose. Prader-willi syndrom...

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Expression of 4 Genes Between Chromosome 15 Breakpoints 1 and 2 and Behavioral Outcomes in Prader-Willi Syndrome

Bittel

Kibiryeva²,

Butler³

2006

Pediatrics

107

View full text Add to dashboard Cite

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“…Dominant negative mutations in the NIPA1 gene were found in patients with autosomal dominant hereditary spastic paraplegia (HSP) [Rainier et al, 2003;Chen et al, 2005]. NIPA1 is an inhibitor of BMP (bone morphogenetic protein), important in axonal outgrowth, and it is thought that dysregulation of BMP lies at the basis of the HSP [Tsang et al, 2009;Botzolakis et al, 2011].…”

Section: Genomic Data On Del15q112mentioning

confidence: 99%

“…NIPA1 is an inhibitor of BMP (bone morphogenetic protein), important in axonal outgrowth, and it is thought that dysregulation of BMP lies at the basis of the HSP [Tsang et al, 2009;Botzolakis et al, 2011]. Unlike dominant negative mutations, there is no indication that a deletion of NIPA1, resulting in haploinsufficiency, would cause HSP [Rainier et al, 2003;Zhao et al, 2008].…”

Section: Genomic Data On Del15q112mentioning

confidence: 99%

Genetic counseling for susceptibility loci and neurodevelopmental disorders: The del15q11.2 as an example

Wolf

Brison

Devriendt

et al. 2013

American J of Med Genetics Pt A

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In recent years, several recurrent copy number variations (CNVs) that confer risk of neurodevelopmental disorders have been identified (e.g., del and dup 16p11.2, del15q13.3, del and dup 1q21.1, del16p13.3, del15q11.2). They are often inherited from an unaffected parent and lack phenotypic specificity. Although there is growing evidence from association studies to consider them as susceptibility CNVs, their clinical utility is debated. Yet the clinician is frequently challenged to deal with these counseling situations without guidelines or consensus. In this report, counseling issues and research opportunities are discussed, with the recurrent 15q11.2 BP1-BP2 (including CYFIP1, NIPA1, NIPA2, TUBGCP5) as an example. Several clinical reports have been published describing patients with del15q11.2 featuring intellectual disability, developmental delay, neurological problems, autism spectrum disorder (ASD), attention problems, speech delay, and dysmorphism. The del15q11.2 was found to be significantly associated with intellectual disability, schizophrenia, epilepsy, and ASD. In this report we discuss how patient-specific and family-specific information may alter the interpretation of del15q11.2 as a contributing factor to the disorder in practical counseling situations. In addition, an association study for ASD in a Belgian Flemish cohort and an overview of reported association studies, clinical reports and genomics data for del15q11.2 are presented.

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“…Interest--ingly, point mutations in NIPA1 (i.e. G 100 R or T 45 R) represent the basis for the insurgence of autosomal dominant HSP (Rainier et al, 2003). Both the glycine and threonine residues are conserved among ortholog NIPA1 channels in different species.…”

Section: Acdp2mentioning

confidence: 99%

Magnesium in the Central Nervous System

Turner

Vink

New Perspectives in Magnesium Research

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NIPA1 Gene Mutations Cause Autosomal Dominant Hereditary Spastic Paraplegia (SPG6)

Cited by 187 publications

References 14 publications

Expression of 4 Genes Between Chromosome 15 Breakpoints 1 and 2 and Behavioral Outcomes in Prader-Willi Syndrome

Expression of 4 Genes Between Chromosome 15 Breakpoints 1 and 2 and Behavioral Outcomes in Prader-Willi Syndrome

Genetic counseling for susceptibility loci and neurodevelopmental disorders: The del15q11.2 as an example

Magnesium in the Central Nervous System

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