ST3GAL3 Mutations Impair the Development of Higher Cognitive Functions

Hu, Hao; Eggers, Katinka; Chen, Wei; Garshasbi, Masoud; Motazacker, Mohammad Mahdi; Wrogemann, Klaus; Kahrizi, Kimia; Tzschach, Andreas; Hosseini, Masoumeh; Bahman, Ideh; Hucho, Tim; Mühlenhoff, Martina; Gerardy‐Schahn, Rita; Najmabadi, Hossein; Ropers, Hans Hilger; Kuß, Andreas W.

doi:10.1016/j.ajhg.2011.08.008

Cited by 94 publications

(120 citation statements)

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“…[10][11][12][13] The introduction of next generation sequencing techniques dramatically changed this scenario, leading to the discovery of a rapidly increasing number of AR-NSID causative genes. In addition to mutations in TECR (MIM 610057), 14 MAN1B1 (MIM 604346), 15 and ST3GAL3 (MIM 606494), 16 32 putative novel genes causative of AR-NSID have been recently reported by Najmabadi et al 17 Of note, the latter studies used an exome sequencing approach targeted to chromosome regions identified by means of linkage analysis, limiting the search of causative genes to families with high imbreeding coefficient, rarely found in western countries.…”

Section: Introductionmentioning

confidence: 99%

TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype

et al. 2012

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Intellectual disability (ID) with autosomal recessive (AR) inheritance is believed to be common; however, very little is known about causative genes and genotype-phenotype correlations. The broad genetic heterogeneity of AR-ID, and its usually nonsyndromic nature make it difficult to pool multiple pedigrees with the same underlying genetic defect to achieve consistent nosology. Nearly all autosomal genes responsible for recessive cognitive disorders have been identified in large consanguineous families from the Middle East, and nonsense mutations in TRAPPC9 have been reported in a total of 5. Although several recurrent phenotypic abnormalities are described in some of these patients, the associated phenotype is usually referred to as nonsyndromic. By means of single-nucleotide polymorphism-array first and then by exome sequencing, we identified a new pathogenic mutation in TRAPPC9 in two Italian sisters born to healthy and apparently nonconsanguineous parents. It consists of a homozygous splice site mutation causing exon skipping with frameshift and premature termination, as confirmed by mRNA sequencing. By detailed phenotypic analysis of our patients, and by critical literature review, we found that homozygous TRAPPC9 loss-of-function mutations cause a distinctive phenotype, characterized by peculiar facial appearance, obesity, hypotonia (all signs resembling a Prader-Willi-like phenotype), moderate-to-severe ID, and consistent brain abnormalities.

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Section: Introductionmentioning

confidence: 99%

TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype

et al. 2012

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“…The disruption of sialyltransferase genes in mice often results in immune and hematologic phenotypes [47][48][49]. Very recently, mutations in the 2-3 sialyltransferase gene ST3GAL3 (OMIM ID: 606494) have been associated with nonsyndromic mental retardation [50]. The exact impact of ST3GAL3 deficiency on brain glycoproteins remains to be established.…”

Section: 2-3 Sia-transferase IIImentioning

confidence: 99%

Diseases of glycosylation beyond classical congenital disorders of glycosylation

Hennet

2012

Biochimica et Biophysica Acta (BBA) - General Subjects

117

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BACKGROUND: Diseases of glycosylation are rare inherited disorders, which are often referred to as congenital disorders of glycosylation (CDG). Several types of CDG have been described in the last decades, encompassing defects of nucleotide-sugar biosynthesis, nucleotide-sugar transporters, glycosyltransferases and vesicular transport. Although clinically heterogeneous, most types of CDG are associated with neurological impairments ranging from severe psychomotor retardation to moderate intellectual disabilities. CDG are mainly caused by defects of N-glycosylation, owing to the simple detection of under-glycosylated serum transferrin by isoelectric focusing. SCOPE OF REVIEW: In the last years, several disorders of O-glycosylation, glycolipid and glycosaminoglycan biosynthesis have been described, which are known by trivial names not directly associated with the family of CDG. The present review outlines 64 gene defects affecting glycan biosynthesis and modifications, thereby underlining the complexity of glycosylation pathways and pointing to unexpected phenotypes and functional redundancies in the control of glycoconjugate biosynthesis. MAJOR CONCLUSIONS: The increasing application of whole-genome sequencing techniques unravels new defects of glycosylation, which are associated to moderate forms of mental disabilities. GENERAL SIGNIFICANCE: The knowledge gathered through the investigation of CDG increases the understanding of the functions associated to protein glycosylation in humans. This article is part of a Special Issue entitled Glycoproteomics.

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“…In affected members of this family, which was ascertained and mapped previously by Najmabadi et al [45] on locus 1p34.1, Hu et al [1] identified two missense homozygous mutations in ST3GAL3 at positions either in exon 2 (c. 38C>A, p.Ala13Asp) or in exon 14 (c.1108G>T, p.Asp370Tyr), which resulted in a loss of activity in the transmembrane and catalytic domains, respectively. The identified genetic alterations in the N-terminal transmembrane domain and C-terminal catalytic domain of sialyltransferase prevented the formation of sialo-glyco conjugates due to mislocalization in cellular compartments other than the golgi apparatus, thereby causing ID in affected members [1,57] …”

Section: St3gal3mentioning

confidence: 99%

“…The ST3GAL3 (ST3 Beta-galactoside Alpha-2, 3-Sialyltransferase 3) gene (OMIM # 606494) was identified by Hu et al [1] as a NS-ARID causing gene in a large consanguineous Iranian family. The ST3GAL3 gene (NCBI RefSeqGene: NG_028196.1) consists of total 25 exons and spans a 223 kb region on chromosome 1p34.1.…”

Section: St3gal3mentioning

confidence: 99%

“…Intellectual disability is a neurodevelopmental disorder characterized by impaired cognitive functions, significant below-average intellectual ability, and functional limitations in some adaptive traits with onset prior to the age of 18 years [1][2]. Sometimes, this disorder manifests in infancy which is manifested by feeding problems, impaired visual acuity, and diminished motor skills, or sometimes in early childhood accompanied by abnormal play and delayed achievement of developmental skills.…”

Section: Introductionmentioning

confidence: 99%

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Genetic Defects Underlie the Non-syndromic Autosomal Recessive Intellectual Disability (NS-ARID)

et al. 2017

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Open Life Sci. 2017; 12: 167-177 IntroductionIntellectual disability is a neurodevelopmental disorder characterized by impaired cognitive functions, significant below-average intellectual ability, and functional limitations in some adaptive traits with onset prior to the age of 18 years [1][2]. Sometimes, this disorder manifests in infancy which is manifested by feeding problems, impaired visual acuity, and diminished motor skills, or sometimes in early childhood accompanied by abnormal play and delayed achievement of developmental skills. Clinically, individuals with an intelligence quotient (IQ) below 70 are considered intellectually disabled. Milder forms of intellectual disability, with IQ between 50 and 70, are more common than moderate and severe forms with IQ below 50 [3]. ID may be a syndrome accompanied by additional physical, metabolic and neurological abnormalities, or non-syndromic, lacking these additional abnormalities [4].Intellectual disability is among the major public health problems because of its frequency (1-3%) in general population, availability of few therapeutic or diagnostic options, and the consequential life-long harm to the affected individuals and their families [5][6]. Moreover, ID is one of the most difficult challenges faced today by clinicians as well as geneticists due to the fact that the causes of this disorder are exceptionally heterogeneous, contributed by both environmental and genetic factors that have been detected in only 50% of the cases [4]. Environmental factors include intoxication during pregnancy, viral infection in the mother, complications of delivery, premature birth, low birth weight and childhood diseases, which are responsible for damage of the nervous system [7]. It has also been reported that 25-50% of ID cases are influenced by genetic factors [8] including chromosomal abnormalities and monogenic defects. Chromosomal abnormalities have been reported in ID; most common being aneuploidies, duplications and submicroscopic deletions [9]. However, among the Abstract:Intellectual disability (ID) is a neurodevelopmental disorder which appears frequently as the result of genetic mutations and may be syndromic (S-ID) or non-syndromic (NS-ID). ID causes an important economic burden, for patient's family, health systems, and society. Identifying genes that cause S-ID can easily be evaluated due to the clinical symptoms or physical anomalies. However, in the case of NS-ID due to the absence of co-morbid features, the latest molecular genetic techniques can be used to understand the genetic defects that underlie it. Recent studies have shown that non-syndromic autosomal recessive (NS-ARID) is extremely heterogeneous and contributes much more than X-linked ID. However, very little is known about the genes and loci involved in NS-ARID relative to X-linked ID, and whose complete genetic etiology remains obscure. In this review article, the known genetic etiology of NS-ARID and possible relationships between genes and the associated molecular pathways of their encode...

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ST3GAL3 Mutations Impair the Development of Higher Cognitive Functions

Cited by 94 publications

References 49 publications

TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype

TRAPPC9-related autosomal recessive intellectual disability: report of a new mutation and clinical phenotype

Diseases of glycosylation beyond classical congenital disorders of glycosylation

Genetic Defects Underlie the Non-syndromic Autosomal Recessive Intellectual Disability (NS-ARID)

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