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GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition

View Article: PubMed Central - PubMed

ABSTRACT

Background: Neuropsychiatric disorders are common forms of disability in humans. Despite recent progress in deciphering the genetics of these disorders, their phenotypic complexity continues to be a major challenge. Mendelian neuropsychiatric disorders are rare but their study has the potential to unravel novel mechanisms that are relevant to their complex counterparts.

Results: In an extended consanguineous family, we identified a novel neuropsychiatric phenotype characterized by severe speech impairment, variable expressivity of attention deficit hyperactivity disorder (ADHD), and motor delay. We identified the disease locus through linkage analysis on 15q21.2, and exome sequencing revealed a novel missense variant in GNB5. GNB5 encodes an atypical β subunit of the heterotrimeric GTP-binding proteins (Gβ5). Gβ5 is enriched in the central nervous system where it forms constitutive complexes with members of the regulator of G protein signaling family of proteins to modulate neurotransmitter signaling that affects a number of neurobehavioral outcomes. Here, we show that the S81L mutant form of Gβ5 has significantly impaired activity in terminating responses that are elicited by dopamine.

Conclusions: We demonstrate that these deficits originate from the impaired expression of the mutant Gβ5 protein, resulting in the decreased ability to stabilize regulator of G protein signaling complexes. Our data suggest that this novel neuropsychiatric phenotype is the human equivalent of Gnb5 deficiency in mice, which manifest motor deficits and hyperactivity, and highlight a critical role of Gβ5 in normal behavior as well as language and motor development in humans.

Electronic supplementary material: The online version of this article (doi:10.1186/s13059-016-1061-6) contains supplementary material, which is available to authorized users.

No MeSH data available.


A novel neuropsychiatric disorder is linked to GNB5 mutation. a Pedigree of the study family. bIdeogram showing a single autozygous interval on chr15 (47,051,884-57,799,765, demarcated by SNPs rs11854077 and rs1280355) that is exclusively shared by the affected members. c Genome-wide linkage analysis shows a single linkage peak on chr15 with LOD ~4 that corresponds to the single autozygous interval shown in (b). A screenshot from the UCSC Genome Browser is shown to highlight the gene content of the linkage peak (GNB5 is boxed in red). dSchematic of GNB5 (transcript NM_ 006578) with the sequence chromatogram of the mutation shown on top. eSchematic of Gβ5 and the location of the missense mutation indicated. f Strong cross-species conservation of the Ser81 residue denoted with a red asterisk (black asterisks in the bottom denote highly conserved residues)
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Fig1: A novel neuropsychiatric disorder is linked to GNB5 mutation. a Pedigree of the study family. bIdeogram showing a single autozygous interval on chr15 (47,051,884-57,799,765, demarcated by SNPs rs11854077 and rs1280355) that is exclusively shared by the affected members. c Genome-wide linkage analysis shows a single linkage peak on chr15 with LOD ~4 that corresponds to the single autozygous interval shown in (b). A screenshot from the UCSC Genome Browser is shown to highlight the gene content of the linkage peak (GNB5 is boxed in red). dSchematic of GNB5 (transcript NM_ 006578) with the sequence chromatogram of the mutation shown on top. eSchematic of Gβ5 and the location of the missense mutation indicated. f Strong cross-species conservation of the Ser81 residue denoted with a red asterisk (black asterisks in the bottom denote highly conserved residues)

Mentions: Through our ongoing effort to identify Mendelian forms of neuropsychiatric disorders in children, we encountered an extended consanguineous Saudi family with multiple members who share the core feature of severe expressive language delay (Additional file 1: Table S1). The five affected members represent three different sibships (Fig. 1). In the first sibship, the index (V:1) is a 10-year-old girl who presented to pediatric neurology with severe expressive and receptive language delay, marked hyperactivity, and school performance issues despite having a normal IQ. She was diagnosed with ADHD according to the DSM IV criteria. Her younger 9-year-old sister (V:2) also had severe expressive and receptive language delay, and although she had no hyperactivity, she met the DSM IV criteria for inattentive type ADHD. Like her sister, she had normal cognitive development. The youngest 3-year-old sister (V:3) was too young to assess for ADHD but, like her other two sisters, had severe language delay. Their first cousin is a 5-year-old girl (IV:1) who initially presented with motor delay and hypotonia but was later found to have severely delayed language development but normal IQ. A distant cousin (IV:6, 9 years old) was not available for formal evaluation but available reports from a different institution showed ADHD diagnosis, severely delayed language acquisition, and mild motor delay.Fig. 1


GNB5 mutation causes a novel neuropsychiatric disorder featuring attention deficit hyperactivity disorder, severely impaired language development and normal cognition
A novel neuropsychiatric disorder is linked to GNB5 mutation. a Pedigree of the study family. bIdeogram showing a single autozygous interval on chr15 (47,051,884-57,799,765, demarcated by SNPs rs11854077 and rs1280355) that is exclusively shared by the affected members. c Genome-wide linkage analysis shows a single linkage peak on chr15 with LOD ~4 that corresponds to the single autozygous interval shown in (b). A screenshot from the UCSC Genome Browser is shown to highlight the gene content of the linkage peak (GNB5 is boxed in red). dSchematic of GNB5 (transcript NM_ 006578) with the sequence chromatogram of the mutation shown on top. eSchematic of Gβ5 and the location of the missense mutation indicated. f Strong cross-species conservation of the Ser81 residue denoted with a red asterisk (black asterisks in the bottom denote highly conserved residues)
© Copyright Policy - OpenAccess
Related In: Results  -  Collection

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getmorefigures.php?uid=PMC5037613&req=5

Fig1: A novel neuropsychiatric disorder is linked to GNB5 mutation. a Pedigree of the study family. bIdeogram showing a single autozygous interval on chr15 (47,051,884-57,799,765, demarcated by SNPs rs11854077 and rs1280355) that is exclusively shared by the affected members. c Genome-wide linkage analysis shows a single linkage peak on chr15 with LOD ~4 that corresponds to the single autozygous interval shown in (b). A screenshot from the UCSC Genome Browser is shown to highlight the gene content of the linkage peak (GNB5 is boxed in red). dSchematic of GNB5 (transcript NM_ 006578) with the sequence chromatogram of the mutation shown on top. eSchematic of Gβ5 and the location of the missense mutation indicated. f Strong cross-species conservation of the Ser81 residue denoted with a red asterisk (black asterisks in the bottom denote highly conserved residues)
Mentions: Through our ongoing effort to identify Mendelian forms of neuropsychiatric disorders in children, we encountered an extended consanguineous Saudi family with multiple members who share the core feature of severe expressive language delay (Additional file 1: Table S1). The five affected members represent three different sibships (Fig. 1). In the first sibship, the index (V:1) is a 10-year-old girl who presented to pediatric neurology with severe expressive and receptive language delay, marked hyperactivity, and school performance issues despite having a normal IQ. She was diagnosed with ADHD according to the DSM IV criteria. Her younger 9-year-old sister (V:2) also had severe expressive and receptive language delay, and although she had no hyperactivity, she met the DSM IV criteria for inattentive type ADHD. Like her sister, she had normal cognitive development. The youngest 3-year-old sister (V:3) was too young to assess for ADHD but, like her other two sisters, had severe language delay. Their first cousin is a 5-year-old girl (IV:1) who initially presented with motor delay and hypotonia but was later found to have severely delayed language development but normal IQ. A distant cousin (IV:6, 9 years old) was not available for formal evaluation but available reports from a different institution showed ADHD diagnosis, severely delayed language acquisition, and mild motor delay.Fig. 1

View Article: PubMed Central - PubMed

ABSTRACT

Background: Neuropsychiatric disorders are common forms of disability in humans. Despite recent progress in deciphering the genetics of these disorders, their phenotypic complexity continues to be a major challenge. Mendelian neuropsychiatric disorders are rare but their study has the potential to unravel novel mechanisms that are relevant to their complex counterparts.

Results: In an extended consanguineous family, we identified a novel neuropsychiatric phenotype characterized by severe speech impairment, variable expressivity of attention deficit hyperactivity disorder (ADHD), and motor delay. We identified the disease locus through linkage analysis on 15q21.2, and exome sequencing revealed a novel missense variant in GNB5. GNB5 encodes an atypical β subunit of the heterotrimeric GTP-binding proteins (Gβ5). Gβ5 is enriched in the central nervous system where it forms constitutive complexes with members of the regulator of G protein signaling family of proteins to modulate neurotransmitter signaling that affects a number of neurobehavioral outcomes. Here, we show that the S81L mutant form of Gβ5 has significantly impaired activity in terminating responses that are elicited by dopamine.

Conclusions: We demonstrate that these deficits originate from the impaired expression of the mutant Gβ5 protein, resulting in the decreased ability to stabilize regulator of G protein signaling complexes. Our data suggest that this novel neuropsychiatric phenotype is the human equivalent of Gnb5 deficiency in mice, which manifest motor deficits and hyperactivity, and highlight a critical role of Gβ5 in normal behavior as well as language and motor development in humans.

Electronic supplementary material: The online version of this article (doi:10.1186/s13059-016-1061-6) contains supplementary material, which is available to authorized users.

No MeSH data available.