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Autosomal-dominant striatal degeneration is caused by a mutation in the phosphodiesterase 8B gene.

ABSTRACT: Autosomal-dominant striatal degeneration (ADSD) is an autosomal-dominant movement disorder affecting the striatal part of the basal ganglia. ADSD is characterized by bradykinesia, dysarthria, and muscle rigidity. These symptoms resemble idiopathic Parkinson disease, but tremor is not present. Using genetic linkage analysis, we have mapped the causative genetic defect to a 3.25 megabase candidate region on chromosome 5q13.3-q14.1. A maximum LOD score of 4.1 (Theta = 0) was obtained at marker D5S1962. Here we show that ADSD is caused by a complex frameshift mutation (c.94G>C+c.95delT) in the phosphodiesterase 8B (PDE8B) gene, which results in a loss of enzymatic phosphodiesterase activity. We found that PDE8B is highly expressed in the brain, especially in the putamen, which is affected by ADSD. PDE8B degrades cyclic AMP, a second messenger implied in dopamine signaling. Dopamine is one of the main neurotransmitters involved in movement control and is deficient in Parkinson disease. We believe that the functional analysis of PDE8B will help to further elucidate the pathomechanism of ADSD as well as contribute to a better understanding of movement disorders.

SUBMITTER: Appenzeller S

PROVIDER: S-EPMC2801755 | biostudies-literature |

REPOSITORIES: biostudies-literature

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A Novel <i>ARL3</i> Gene Mutation Associated With Autosomal Dominant Retinal Degeneration.

Project description:Despite major progress in the discovery of causative genes, many individuals and families with inherited retinal degenerations (IRDs) remain without a molecular diagnosis. We applied whole exome sequencing to identify the genetic cause in a family with an autosomal dominant IRD. Eye examinations were performed and affected patients were studied with electroretinography and kinetic and chromatic static perimetry. Sequence variants were analyzed in genes (n = 271) associated with IRDs listed on the RetNet database. We applied a stepwise filtering process involving the allele frequency in the control population, in silico prediction tools for pathogenicity, and evolutionary conservation to prioritize the potential causal variant(s). Sanger sequencing and segregation analysis were performed on the proband and other family members. The IRD in this family is expressed as a widespread progressive retinal degeneration with maculopathy. A novel heterozygous variant (c.200A > T) was identified in the ARL3 gene, leading to the substitution of aspartic acid to valine at position 67. The Asp67 residue is evolutionary conserved, and the change p.Asp67Val is predicted to be pathogenic. This variant was segregated in affected members of the family and was absent from an unaffected individual. Two previous reports of a de novo missense mutation in the ARL3 gene, each describing a family with two affected generations, are the only examples to date of autosomal dominant IRD associated with this photoreceptor gene. Our results, identifying a novel pathogenic variant in ARL3 in a four-generation family with a dominant IRD, augment the evidence that the ARL3 gene is another cause of non-syndromic retinal degeneration.

| S-EPMC8416110 | biostudies-literature

Run-on mutation in the PAX6 gene and chorioretinal degeneration in autosomal dominant aniridia.

Project description:PurposeTo identify the causative paired box 6 (PAX6) mutation in a family with autosomal dominant aniridia.MethodsA family with autosomal dominant aniridia with three affected individuals in two generations was investigated for the causative PAX6 mutation by single strand conformation polymorphism (SSCP) followed by sequencing of genomic DNA from peripheral blood.ResultsA novel PAX6 mutation in the donor splice site of intron 12 was identified in all three affected individuals from the family. The automated splice site analysis web interface indicated a disturbance of splicing and it was predicted that this mutation could lead to an elimination of the normal stop codon and an abnormal 3' elongation of the mRNA.ConclusionsWe report a novel PAX6 mutation in autosomal dominant aniridia that presumably affects splicing. The presence of chorioretinal degeneration in one of the affected individual raises the possibility that run-on mutations are associated with chorioretinal involvement in aniridia.

| S-EPMC3103739 | biostudies-literature

Autosomal dominant eccentric core disease caused by a heterozygous mutation in the MYH7 gene.

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| S-EPMC4173876 | biostudies-literature

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| S-EPMC5358799 | biostudies-literature

Autosomal dominant familial neurohypophyseal diabetes insipidus caused by a novel nonsense mutation in AVP-NPII gene.

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| S-EPMC6601387 | biostudies-literature

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| S-EPMC4342361 | biostudies-literature

Autosomal dominant hypoparathyroidism caused by germline mutation in GNA11: phenotypic and molecular characterization.

Project description:Most cases of autosomal dominant hypoparathyroidism (ADH) are caused by gain-of-function mutations in CASR or dominant inhibitor mutations in GCM2 or PTH.Our objectives were to identify the genetic basis for ADH in a multigenerational family and define the underlying disease mechanism.Here we evaluated a multigenerational family with ADH in which affected subjects had normal sequences in these genes and were shorter than unaffected family members.We collected clinical and biochemical data from 6 of 11 affected subjects and performed whole-exome sequence analysis on DNA from two affected sisters and their affected father. Functional studies were performed after expression of wild-type and mutant G?11 proteins in human embryonic kidney-293-CaR cells that stably express calcium-sensing receptors.Whole-exome-sequencing followed by Sanger sequencing revealed a heterozygous mutation, c.179G>T; p.R60L, in GNA11, which encodes the ?-subunit of G11, the principal heterotrimeric G protein that couples calcium-sensing receptors to signal activation in parathyroid cells. Functional studies of G?11 R60L showed increased accumulation of intracellular concentration of free calcium in response to extracellular concentration of free calcium with a significantly decreased EC50 compared with wild-type G?11. By contrast, R60L was significantly less effective than the oncogenic Q209L form of G?11 as an activator of the MAPK pathway. Compared to subjects with CASR mutations, patients with GNA11 mutations lacked hypercalciuria and had normal serum magnesium levels.Our findings indicate that the germline gain-of-function mutation of GNA11 is a cause of ADH and implicate a novel role for GNA11 in skeletal growth.

| S-EPMC4154081 | biostudies-literature

Disease progression in autosomal dominant cone-rod dystrophy caused by a novel mutation (D100G) in the GUCA1A gene.

Project description:PURPOSE:To document longitudinal fundus autofluorescence (FAF) and electroretinogram (ERG) findings in a family with cone-rod dystrophy (CRD) caused by a novel missense mutation (D100G) in the GUCA1A gene. METHODS:Observational case series. RESULTS:Three family members 26-49 years old underwent complete clinical examinations. In all patients, funduscopic findings showed intraretinal pigment migration, loss of neurosensory retinal pigment epithelium, and macular atrophy. FAF imaging revealed the presence of a progressive hyperautofluorescent ring around a hypoautofluorescent center corresponding to macular atrophy. Full-field ERGs showed a more severe loss of cone than rod function in each patient. Thirty-hertz flicker responses fell far below normal limits. Longitudinal FAF and ERG findings in one patient suggested progressive CRD. Two more advanced patients exhibited reduced rod response consistent with disease stage. Direct sequencing of the GUCA1A gene revealed a new missense mutation, p.Asp100Gly (D100G), in each patient. CONCLUSION:Patients with autosomal dominant CRD caused by a D100G mutation in GUCA1A exhibit progressive vision loss early within the first decade of life identifiable by distinct ERG characteristics and subsequent genetic testing.

| S-EPMC3974164 | biostudies-literature

Impaired growth and intracranial calcifications in autosomal dominant hypocalcemia caused by a GNA11 mutation.

Project description:Autosomal dominant hypocalcemia (ADH) is characterized by hypocalcemia and inappropriately low PTH concentrations. ADH type 1 is caused by activating mutations in the calcium-sensing receptor (CASR), a G-protein-coupled receptor signaling through ?11 (G?11) and ?q (G?q) subunits. Heterozygous activating mutations in GNA11, the gene encoding G?11, underlie ADH type 2. This study describes disease characteristics in a family with ADH caused by a gain-of-function mutation in GNA11.A three-generation family with seven members (3 adults, 4 children) presenting with ADH.Biochemical parameters of calcium metabolism, clinical, genetic and brain imaging findings were analyzed.Sanger sequencing revealed a heterozygous GNA11 missense mutation (c.1018G>A, p.V340M) in all seven hypocalcemic subjects, but not in the healthy family members (n=4). The adult patients showed clinical symptoms of hypocalcemia, while the children were asymptomatic. Plasma ionized calcium ranged from 0.95 to 1.14mmol/L, yet plasma PTH was inappropriately low for the degree of hypocalcemia. Serum 25OHD was normal. Despite hypocalcemia 1,25(OH)2D and urinary calcium excretion were inappropriately in the reference range. None of the patients had nephrocalcinosis. Two adults and one child (of the two MRI scanned children) had distinct intracranial calcifications. All affected subjects had short stature (height s.d. scores ranging from -3.4 to -2.3 vs -0.5 in the unaffected children).The identified GNA11 mutation results in biochemical abnormalities typical for ADH. Additional features, including short stature and early intracranial calcifications, cosegregated with the mutation. These findings may indicate a wider role for G?11 signaling besides calcium regulation.

| S-EPMC5149394 | biostudies-literature

Autosomal-dominant retinitis pigmentosa caused by a mutation in SNRNP200, a gene required for unwinding of U4/U6 snRNAs.

Project description:Mutations in genes associated with the U4/U6-U5 small nuclear ribonucleoprotein (snRNP) complex of the spliceosome are implicated in autosomal-dominant retinitis pigmentosa (adRP), a group of progressive retinal degenerative disorders leading to visual impairment, loss of visual field, and even blindness. We recently assigned a locus (RP33) for adRP to 2cen-q12.1, a region that harbors the SNRNP200 gene encoding hBrr2, another U4/U6-U5 snRNP component that is required for unwinding of U4/U6 snRNAs during spliceosome activation and for disassembly of the spliceosome. Here, we report the identification of a missense mutation, c.3260C>T (p.S1087L), in exon 25 of the SNRNP200 gene in an RP33-linked family. The c.3260C>T substitution showed complete cosegregation with the retinitis pigmentosa (RP) phenotype over four generations, but was absent in a panel of 400 controls. The p.S1087L mutation and p.R1090L, another adRP-associated allele, reside in the "ratchet" helix of the first of two Sec63 domains implicated in the directionality and processivity of nucleic acid unwinding. Indeed, marked defects in U4/U6 unwinding, but not U4/U6-U5 snRNP assembly, were observed in budding yeast for the analogous mutations (N1104L and R1107L) of the corresponding Brr2p residues. The linkage of hBrr2 to adRP suggests that the mechanism of pathogenesis for splicing-factor-related RP may fundamentally derive from a defect in hBrr2-dependent RNA unwinding and a consequent defect in spliceosome activation.

| S-EPMC2775825 | biostudies-literature

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