Split-hand and split-foot deformity inherited as an autosomal recessive trait

A intermarried consanguineous family with split-hand and -foot deformity occurring in two sibship is presented. Both the sibship resulted from marriage between first cousins. This report, together with those of Ray (1960) and Freire-Maia (1971), further demonstrates that split-hand and -foot deformity can be inherited as an autosomal recessive trait.     

Using next-generation sequencing as a genetic diagnostic tool in rare autosomal recessive neurologic Mendelian disorders

Next-generation sequencing was used to investigate 9 rare Chinese pedigrees with rare autosomal recessive neurologic Mendelian disorders. Five probands with ataxia-telangectasia and 1 proband with chorea-acanthocytosis were analyzed by targeted gene sequencing. Whole-exome sequencing was used to investigate 3 affected individuals with Joubert syndrome, nemaline myopathy, or spastic ataxia Charlevoix-Saguenay type. A list of known and novel candidate variants was identified for each causative gene. All variants were genetically verified by Sanger sequencing or quantitative polymerase chain reaction with the strategy of disease segregation in related pedigrees and healthy controls. The advantages of using next-generation sequencing to diagnose rare autosomal recessive neurologic Mendelian disorders characterized by genetic and phenotypic heterogeneity are demonstrated. A genetic diagnostic strategy combining the use of targeted gene sequencing and whole-exome sequencing with the aid of next-generation sequencing platforms has shown great promise for improving the diagnosis of neurologic Mendelian disorders.     

Crigler-Najjar syndrome type II is inherited both as a dominant and as a recessive trait

Crigler-Najjar syndrome type II (CN-II) is caused by a severely reduced hepatic activity of bilirubin UDP-glucuronosyltransferase (UGT). Recently, by the analysis of the genetic background of CN-II patients, it has been clarified that the patients carry homozygous missense mutations or nonsense plus missense mutations on the gene for UGT, and CN-II was inherited as an autosomal recessive trait. We encountered a new case which had a nonsense mutation caused by a single nucleotide substitution on one allele. This indicates that CN-II is also inherited as a dominant trait as well as a recessive trait. Expression study in vitro strongly suggests that the disease in this case is caused by a dominant negative mutation by forming a heterologous subunit structure.      

A recessive Mendelian model to predict carrier probabilities of DFNB1 for nonsyndromic deafness

Mutations in the DFNB1 locus, where two connexin genes are located (GJB2 and GJB6), account for half of congenital cases of nonsyndromic autosomal recessive deafness. Because of the high frequency of DFNB1 gene mutations and the availability of genetic diagnostic tests involving these genes, they are the best candidates to develop a risk prediction model of being hearing impaired. People undergoing genetic counseling are normally interested in knowing the probability of having a hearing impaired child given his/her family history. To address this, a Mendelian model that predicts the probability of being a carrier of DFNB1 mutations, using family history of deafness, has been developed. This probability will be useful as additional information to decide whether or not a genetic test should be performed. This model incorporates Mendelian mode of inheritance, the age of onset of the disease, and the current age of hearing family members. The carrier probabilities are obtained using Bayes' theorem, in which mutation prevalence is used as the prior distribution. We have validated our model by using information from 305 families affected with congenital or progressive nonsyndromic deafness, in which genetic analysis of GJB2 and GJB6 had already been performed. This model works well, especially in homozygous carriers, showing a high discriminative power. This indicates that our proposed model can be useful in the context of clinical counseling of autosomal recessive disorders.     

Association between schizophrenia and DRD3 or HTR2 receptor gene variants

Schizophrenia is a severe and common psychiatric disorder afflicting 1% of the world population. A role of many neurotransmitter receptors in schizophrenia was suggested by an association with several polymorphisms located in their coding regions. In this study we examined the contribution of the T-102C and A-206G transitions in the 5-HTR2a and DRD3 receptor genes respectively to genetic susceptibility and phenotypic expression of schizophrenia disorder within the Greek population. We determined by PCR and RFLP analysis the genotype for the above polymorphisms in 114 schizophrenic hospitalized individuals and 192 control samples. In contrast to previous reports from large European multicentre studies, which indicate significant correlation between schizophrenia and C-102 allele of the T-102C polymorphism, in this study we observed a statistically significant overall association between the disorder and allele T-102 (P<0.0001, odds ratio (OR)=2.11, 95% CI=1.48-3.02). We also found a highly significant excess of the T-102/C-102 and C-102/C-102 genotypes in the normal group (P<0.001). Comparison of the patients with the controls for the DRD3 polymorphism (A-206G transition) showed marginally nonsignificant differences in the genotypic (P=0.054) and no significance in the allelic (P=0.163) frequencies. However, the A-206/A-206 genotype seems to positively contribute to the disorder appearance, when compared to A-206/G-206 as genotype base line risk (P=0.016, OR=1.88, 95% CI=1.09-3.26). In conclusion, from genetic association analysis of this schizophrenic population, a significant association is clearly determined between the HTR2 genetic polymorphism and the presence of schizophrenic disorder, manifested as increased risk of schizophrenia for carriers of the T-102 allele.     

Cerebellar hypoplasia and quadrupedal locomotion in humans as a recessive trait mapping to chromosome 17p

Background

Congenital hereditary non‐progressive hypoplasia of the cerebellum is a rare condition, frequently associated with other neuropathology such as lissencephaly. Clinically, the condition is associated with variable degrees of mental retardation, microcephaly, seizures, and movement disorders due to ataxia. In severe cases, patients are unable to ambulate independently, but nevertheless do use bipedal locomotion.

Methods and Results

Here we present a family with seven affected members, five of whom never learned to walk on two legs but have fully adapted to quadrupedal palmigrade locomotion. These subjects show signs of cerebellar ataxia and are mentally retarded. MRI analysis demonstrated hypoplasia of the cerebellum and the cerebellar vermis as well as a small nucleus dentatus and a thin corpus callosum but no other malformations. We show, by a genome‐wide linkage scan, that quadrupedal locomotion is a recessive trait linked to chromosome 17p.

Conclusions

Our findings have implications for understanding the neural mechanism mediating bipedalism, and, perhaps, the evolution of this unique hominid trait.     

Dopamine D3 receptor and schizophrenia: a widened scope for the immune hypothesis

Schizophrenia may be related to immunity as is suggested by many findings of altered immune parameters in schizophrenic patients. How immune alterations might be involved in the emergence of psychosis is still unclear. Clearly, however, the dopamine hypothesis has been confirmed in recent studies, which implies a crucial role for dopamine and the dopamine D2 receptor (D2R) within the pathogenesis of schizophrenia. The Dopamine D3 receptor (D3R) is considered to have autoreceptor properties modulating the synthesis and release of dopamine, thereby possibly antagonizing the dopamine D2-receptor-mediated effects of dopamine and has been found reduced in schizophrenic patients during acute psychosis and increasing in the advent of negative schizophrenic symptoms. Immune parameters apparently influence the expression of dopamine receptors by means of their capability to induce regulatory factors involved in the expression of dopamine receptor subtypes, such as the neurotrophins, associations of which with psychosis have been reported repeatedly. Here, we propose a hypothesis of immune alterations that influence the production of distinct neurotrophins such as BDNF and NGF that, as animal studies suggest, influence the expression of dopamine receptor subtypes. This mechanism could result in a decrease of D3R and a consecutive relative preponderance of D2R and thereby connect immune alterations and schizophrenia.     

Association between the dopamine D3 receptor gene locus (DRD3) and unipolar affective disorder

Dopamine neurotransmission has been implicated in the pathophysiology of schizophrenia and, more recently, affective disorders. Among the dopamine receptors, D3 can be considered as particularly related to affective disorders due to its neuroanatomical localization in the limbic region of the brain and its relation to the serotoninergic activity of the CNS. The possible involvement of dopamine receptor D3 in unipolar (UP) major depression was investigated by a genetic association study of the D3 receptor gene locus (DRD3) on 36 UP patients and 38 ethnically matched controls. An allelic association of DRD3 (Bal I polymorphism) and UP illness was observed, with the Gly-9 allele (allele '2', 206/98 base-pairs long) being more frequent in patients than in controls (49% vs 29%, P < 0.02). The genotypes containing this allele (1-2 and 2-2) were found in 75% of patients vs 50% of controls (P < 0.03, odds ratio = 3.00, 95% CI = 1.12-8.05). The effect of the genotype remained significant (P < 0.02) after sex and family history were controlled by a multiple linear regression analysis. These results further support the hypothesis that dopaminergic mechanisms may be implicated in the pathogenesis of affective disorder. More specifically, the '2' allele of the dopamine receptor D3 gene seems to be associated with unipolar depression and can be considered as a 'phenotypic modifier' for major psychiatric disorders.     

Heterozygosity for a Mendelian disorder as a risk factor for complex disease

While genetic diseases are generally classified as being either 'simple' monogenic or 'complex' polygenic, the distinction between Mendelian and complex disorders is becoming increasingly blurred. Mendelian disorders may demonstrate qualities more typical of multifactorial diseases through shared clinical presentations, the effect of genetic modifiers, moonlighting proteins, synergistic heterozygosity, disease manifestations in heterozygotes and situations where heterozygosity for a 'simple' disorder proves to be a risk factor for seemingly unrelated complex diseases. A recent example of the last instance is the observation that mutations in glucocerebrosidase, the enzyme deficient in Gaucher disease, may be a risk factor for the development of Parkinson disease and other synucleinopathies. Insights gleaned from the study of Mendelian disorders may ultimately lead to a better understanding of factors influencing complex diseases.     

Mendelian randomization highlights insomnia as a risk factor for pain diagnoses

Study ObjectiveInsomnia has been linked to acute and chronic pain conditions; however, it is unclear whether such relationships are causal. Recently, a large number of genetic variants have been discovered for both insomnia and pain through genome-wide association studies (GWASs) providing a unique opportunity to examine the evidence for causal relationships through the use of the Mendelian randomization paradigm.MethodsTo elucidate the causality between insomnia and pain, we performed bidirectional Mendelian randomization analysis in FinnGen, where clinically diagnosed ICD-10 categories of pain had been evaluated. In addition, we used measures of self-reported insomnia symptoms. We used endpoints for pain in the FinnGen Release 5 (R5) (N = 218,379), and a non-overlapping sample for insomnia (UK Biobank (UKBB) and 23andMe, N = 1,331,010 or UKBB alone N = 453,379). We assessed the robustness of results through conventional Mendelian randomization sensitivity analyses.ResultsGenetic liability to insomnia symptoms increased the odds of reporting pain (odds ratio (OR) [95% confidence interval (CI)] = 1.47 [1.38–1.58], p = 4.12 × 10⁻²⁸). Manifested pain had a small effect on increased risk for insomnia (OR [95% CI] = 1.04 [1.01–1.07], p < 0.05). Results were consistent in sensitivity analyses.ConclusionsOur findings support a bidirectional causal relationship between insomnia and pain. These data support a further clinical investigation into the utility of insomnia treatment as a strategy for pain management and vice versa.     

Dopamine receptor hetero-oligomerization: a hypothesis for behavioral sensitization to psychostimulants

Repeated psychostimulant pretreatment can induce behavioral sensitization. Many previous studies have demonstrated that receptors of the dopamine and other neurotransmitter systems are involved in the sensitization process, however, the precise mechanism of this interaction is still unknown. We propose the hypothesis that oligomerization of the dopamine receptors and analogs from other neurotransmitter systems may contribute, at least in part, to psychostimulant-induced behavioral sensitization. Psychostimulant exposure can enhance central dopamine release, which can increase oligomerization of the dopamine receptors with their analogs. Receptor oligomerization can enhance the functional properties of the receptors and affect receptor degradation, which may be related to the behavioral augmentation which characterizes the sensitized state and produces the persistence of behavioral sensitization. The proposed receptor hetero-oligomerization model may provide a new direction in the exploration of the functionally critical sensitization phenomenon.     

Dopamine D3 receptor: A neglected participant in Parkinson Disease pathogenesis and treatment?

Parkinson disease (PD) is a neurodegenerative disorder characterized by motor and non-motor symptoms which relentlessly and progressively lead to substantial disability and economic burden. Pathologically, these symptoms follow the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc) associated with abnormal α-synuclein (α-Syn) deposition as cytoplasmic inclusions called Lewy bodies in pigmented brainstem nuclei, and in dystrophic neurons in striatal and cortical regions (Lewy neurites). Pharmacotherapy for PD focuses on improving quality of life and primarily targets dopaminergic pathways. Dopamine acts through two families of receptors, dopamine D1-like and dopamine D2-like; dopamine D3 receptors (D3R) belong to dopamine D2 receptor (D2R) family. Although D3R’s precise role in the pathophysiology and treatment of PD has not been determined, we present evidence suggesting an important role for D3R in the early development and occurrence of PD. Agonist activation of D3R increases dopamine concentration, decreases α-Syn accumulation, enhances secretion of brain derived neurotrophic factors (BDNF), ameliorates neuroinflammation, alleviates oxidative stress, promotes neurogenesis in the nigrostriatal pathway, interacts with D1R to reduce PD associated motor symptoms and ameliorates side effects of levodopa (L-DOPA) treatment. Furthermore, D3R mutations can predict PD age of onset and prognosis of PD treatment. The role of D3R in PD merits further research. This review elucidates the potential role of D3R in PD pathogenesis and therapy.     

Dopamine D3 receptor regulates basal but not amphetamine-induced changes in pain sensitivity in mice

Pain is a complex and subjective experience that involves not only the transduction of noxious stimuli by nociceptive fibers, but also the cognitive and emotional processing by the brain. Previous studies on the transmission of nociception suggest that the activation of mesolimbic dopamine (DA) system plays an important role in mediating the suppression of tonic pain. The aim of the current study was to examine the role of DA D3 receptor in modulating basal and amphetamine-induced changes in pain sensitivity in mice. We used wild-type and D3 receptor mutant mice and determined allodynia induced by both noxious heat (radiant heat) and mechanical (von Frey hair) stimuli. We show that D3 receptor mutant mice exhibit hypoalgesia in both the tail-flick test and von Frey hair test compared to wild-type mice. Amphetamine-induced hyperalgesia in both D3 receptor mutant and wild-type mice in the tail-flick test and von Frey hair test. There was no significantly difference in the relative change in pain sensitivity between wild-type and D3 receptor mutant mice in both the tail-flick test and von Frey hair test following amphetamine administration. These results suggest that the D3 receptor regulates the transmission of nociception. Moreover, amphetamine can lower pain threshold in mice.     

Dopamine D3 receptor knock-out mice display deficits in locomotor sensitization after chronic morphine administration

Locomotor sensitization is the progressive and enduring enhancement of locomotion induced by stimulants such as drugs, which alter rodent locomotion in a long-standing manner. The dopamine D3 receptor has been reported to play a role in morphine addiction. The aim of the present study was to investigate the role of dopamine D3 receptor in the morphine induced locomotor sensitization using dopamine D3 receptor knock-out mice. The dopamine D3 receptor knock-out mice did not display an enhanced behavioral response to acute morphine administration or develop an increased rate of locomotor sensitization to intermittent morphine administration. When 2 mg/kg naloxone was co-administered with 10 mg/kg morphine, morphine-induced locomotion sensitization in wild-type mice was significantly blocked while the locomotion in the D3 receptor knock-out mice was decreased. Then the wild-type mice were administered with dopamine D3 antagonist nafadotride. It was found that co-administration of morphine with nafadotride could effectively suppress the level of morphine induced behavioral sensitization. It was concluded that a loss of the dopamine D3 receptor gene may inhibit acute morphine induced hyperlocomotor activity and chronic morphine induced behavioral sensitization.     

Gender-specific molecular heterosis of dopamine D2 receptor gene (DRD2) for smoking in schizophrenia

We examined the genetic effect of DRD2 A1 allele in 167 Korean schizophrenics in relation to their smoking habit. Although there was no apparent difference in the genotype distributions of DRD2 gene among the female schizophrenics (n = 66), the male counterpart (n = 101) showed significant differences in their genotype distributions. The comparison between male smoking and non-smoking patients showed the difference in genotype distribution (P = 0.010) with a higher prevalence of A1 allele (P = 0.020) and frequency of heterozygotes (P = 0.005), but not frequency of the A1 allele. The A1A2 heterozygotes male showed significantly higher smoking rate compared to the A1A1 or A2A2 homozygotes male, and non-smokers were deficient in heterozygotes. By contrast, among female schizophrenics, the heterozygotes showed a lower smoking rate than homozygotes and there were more heterozygotes in non-smokers. The deviation from Hardy-Weinberg expectations was observed in male and female non-smokers showing quite opposite profiles. Highly significant differences were seen between male and female non-smokers in A1 prevalence (P = 0.001), genotype distribution (P = 0.00011), and frequency of heterozygotes (P = 0.00003), but not in A1 frequency. The analyses from both male and female as one group showing no significant difference in the genotype distributions between smokers and non-smokers could be explained by the gender difference in the genetic effect of DRD2 A1 allele. Our findings present the gender-specific molecular heterosis of DRD2 gene in relation specifically to the smoking status of schizophrenic patients. They indicate the importance of heterosis and gender effects that should be taken into consideration for the association studies.