A new chromosome anomaly in a patient with apparent C (trigonocephaly) syndrome.
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Abnormalities, Multiple↗
Biomedical subjects
Robert P Erickson
Publications and source records attributed to Robert P Erickson.
Number of risk genotypes is a risk factor for major depressive disorder: a case control study.
BACKGROUND: The objective of the study was to determine the genetic basis of Major Depressive Disorder, and the capacity to respond to antidepressant treatment. An association study of 21 candidate polymorphisms relevant to monoamine function and the mechanism of antidepressant response was conducted in 3 phenotypically distinct samples: a group with chronic or recurrent depression unable to respond to antidepressants (non-responders) (n = 58), a group capable of symptomatic improvement with or without treatment (responders) (n = 39), and volunteer controls (n = 85). The responders and non-responders constituted a larger group of depressed subjects. METHODS: A candidate gene approach was employed to asses the genetics basis of Major Depressive Disorder. The genotypic frequencies of selected polymorphisms were compared between the controls and depressed subjects. To asses the genetics basis of the capacity to respond to antidepressant treatment, the responders were compared to the non-responders. Candidate genes were chosen based on functional studies and proximity to whole genome linkage findings in the literature. Risk genotypes were identified by previous functional studies and association studies. RESULTS: A statistically significant difference in genotype frequency for the SLC6A4 intron 2 VNTR was detected between the subjects with a history of depression and controls (p = 0.004). Surprisingly, a statistically significant difference was detected between responders and non-responders for the DRD4 exon III VNTR genotype frequencies (p = 0.009). Furthermore, a difference between the controls and depressed subjects as well as between the controls and non-responders was detected for the number and distribution of risk genotypes in each group. CONCLUSION: An association between several monoamine-related genes and Major Depressive Disorder is supported. The data suggest that the two depressive phenotypes are genetically different, inferring that the genetic basis for the capacity to respond to standard antidepressant treatment, and the genetic susceptibility to Major Depressive Disorder may be independent. In addition, a proof of concept is provided demonstrating that the number of risk genotypes may be an indication of susceptibility of major depressive disorder and the severity of the disorder.
Journal Article↗
Allopregnanolone treatment, both as a single injection or repetitively, delays demyelination and enhances survival of Niemann-Pick C mice.
Niemann-Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is thought to result from deficient intracellular cholesterol and/or ganglioside trafficking. We have investigated the effects of allopregnanolone treatments on survival, weight loss, motor function, magnetic resonance imaging (MRI), and neuropathology in the mouse model of NPC (Npc1(-/-) mice). We confirmed previous results showing that a single injection of 250 microg of allopregnanolone on postnatal day 7 significantly extended the life span of Npc1(-/-) mice. This caused a marked difference in the weight curves of the treated mice but no statistical difference in the Rota-Rod performance. T2-weighted MRI and diffusion tensor imaging (DTI) of treated mice showed values of signal intensity and fractional anisotropy closer to those of wild-type mice than those of untreated Npc1(-/-) mice. Neuropathology showed that day-7 treatment markedly suppressed astrocyte reaction and significantly reduced microglial activation. Furthermore, the steroid treatment also increased myelination in brains of Npc1(-/-) mice. Similar effects of allopregnanolone treatment were observed in Npc1(-/-), mdr1a(-/-) double-mutant mice, which have a deficient blood-brain barrier, resulting in increased steroid uptake. The effects on survival and weight loss of a single injection on day 7 followed by injections every 2 weeks were also evaluated in Npc1(-/-) mice, and the beneficial effects were found to be greater than with the single injection at day 7. We conclude that allopregnanolone treatment significantly ameliorates several symptoms of NPC in Npc1(-/-) mice, presumably by effects on myelination or neuronal connectivity.
2',3'-Cyclic-Nucleotide Phosphodiesterases↗
Homozygous HOXA1 mutations disrupt human brainstem, inner ear, cardiovascular and cognitive development.
We identified homozygous truncating mutations in HOXA1 in three genetically isolated human populations. The resulting phenotype includes horizontal gaze abnormalities, deafness, facial weakness, hypoventilation, vascular malformations of the internal carotid arteries and cardiac outflow tract, mental retardation and autism spectrum disorder. This is the first report to our knowledge of viable homozygous truncating mutations in any human HOX gene and of a mendelian disorder resulting from mutations in a human HOX gene critical for development of the central nervous system.
Autistic Disorder↗
Agenesis of tibia with bifid femur, congenital heart disease, and cleft lip with cleft palate or tracheoesophageal fistula: possible variants of Gollop-Wolfgang complex.
Two patients with bifurcation of one femur, ipsilateral absence of tibia and one partially formed tibia, or bilateral absent tibiae, club feet with normal or nearly normal digits, congenital heart disease and, in one case, tracheoesophageal fistula; in the second, cleft lip and cleft palate and enlarged head with increased fluid and lissencephaly, are described. These appear to be unique combinations of defects but overlap with the Gollop-Wolfgang complex is present, particularly with the case of possible Gollop-Wolfgang described by Raas-Rothschild et al.
Abnormalities, Multiple↗
Liver disease with altered bile acid transport in Niemann-Pick C mice on a high-fat, 1% cholesterol diet.
Cholestatic hepatitis is frequently found in Niemann-Pick C (NPC) disease. We studied the influence of diet and the low density lipoprotein receptor (LDLR, Ldlr in mice, known to be the source of most of the stored cholesterol) on liver disease in the mouse model of NPC. Npc1-/- mice of both sexes, with or without the Ldlr knockout, were fed a 18% fat, 1% cholesterol ("high-fat") diet and were evaluated by chemical and histological methods. Bile acid transporters [multidrug resistance protein (Mrps) 1-5; Ntcp, Bsep, and OatP1, 2, and 4] were quantitated by real-time RT-PCR. Many mice died prematurely (within 6 wk) with hepatomegaly. Histopathology showed an increase in macrophage and hepatocyte lipids independent of Ldlr genotype. Non-zone-dependent diffuse fibrosis was found in the surviving mice. Serum alanine aminotransferase was elevated in Npc1-/- mice on the regular diet and frequently became markedly elevated with the high-fat diet. Serum cholesterol was increased in the controls but not the Npc1-/- mice on the high-fat diet; it was massively increased in the Ldlr-/- mice. Esterified cholesterol was greatly increased by the high-fat diet, independent of Ldlr genotype. gamma-Glutamyltransferase was also elevated in Npc1-/- mice, more so on the high-fat diet. Mrps 1-5 were elevated in Npc1-/- liver and became more elevated with the high-fat diet; Ntcp, Bsep, and OatP2 were elevated in Npc1-/- liver and were suppressed by the high-fat diet. In conclusion, Npc1-/- mice on a high-fat diet provide an animal model of NPC cholestatic hepatitis and indicate a role for altered bile acid transport in its pathogenesis.
Animals↗
Correlation of susceptibility to 6-aminonicotinamide and hydrocortisone-induced cleft palate.
Our previous genome-wide Quantitative Trait Locus (QTL) mapping study using mouse A/J by C57BL/6J recombinant inbred (RI) lines suggested several chromosomal regions contain genes influencing susceptibility to phenytoin (PT)-induced cleft lip with or without cleft palate [CL(P)] and 6-aminonicotinamide (6-AN)-induced isolated cleft palate (CP). Importantly, the same chromosomal regions but different RI parental strain alleles were sometimes implicated in susceptibility to these different kinds of orofacial clefting. Here we report the susceptibility to hydrocortisone (HC)-induced CP in these RI lines. We treated pregnant females with HC and studied the incidence of CP in day 17 fetuses. RI lines showed highly correlated responses to HC and 6-AN. The A/J parental line and five RI lines showed very high levels of clefting in response to both of these teratogens. The C57BL/6J parental line and five other RI lines exhibited low incidence of CP for these teratogens. In contrast, there was no significant correlation between incidence of PT-induced CL(P) and HC-induced CP.
6-Aminonicotinamide↗
Diffusion tensor imaging in Niemann-Pick Type C disease.
Niemann-Pick Type C disease is a homozygous recessive disorder resulting in errant intracellular cholesterol metabolism and the accumulation of intracellular unesterified cholesterol and sphingolipids. Although no current effective treatment exists for Niemann-Pick Type C disease, a number of therapies are under development in animal models. As therapies are brought into clinical trials, it will be extremely helpful to have a reliable means to track the progression of the disease and to monitor its response to therapy. In this effort, diffusion tensor imaging has been applied to investigate the white matter in a Niemann-Pick Type C patient, and the results compared to those from age-matched control subjects. Diffusion tensor imaging enables quantitative measurement of water diffusion in white matter, which is sensitive to the architecture and integrity of the tissue. Compared with control subjects, significant reductions in fractional anisotropy values were observed in regions of white matter, most prominently in the corpus callosum. The results from this case study suggest that diffusion tensor imaging may allow progression of the disease to be quantitatively measured and may be able to play a role as a surrogate marker in clinical trials.
Adolescent↗
DNA constructs designed to produce short hairpin, interfering RNAs in transgenic mice sometimes show early lethality and an interferon response.
Arylamine N-acetyltransferase (NAT) genes were targeted for inhibition using short hairpin RNA (shRNA) using two different RNA polymerase III promoters. Constructs were developed for NAT1 and NAT2, the endogenous mouse genes, and for human NAT1. There were fetal and neonatal deaths with these constructs, perhaps due in part to an interferon response as reflected in increases in oligoadenylate synthetase I mRNA levels. Seven out of 8 founders with the U6 promoter generated offspring but only 2 gave positive offspring. Out of 15 founders for H1 promoted constructs, only 4 had positive offspring. When transgenic lines were successfully established, the expression of the targeted genes was variable between animals and was not generally inhibitory.
Acetyltransferases↗
Foxc2 is expressed in developing lymphatic vessels and other tissues associated with lymphedema-distichiasis syndrome.
The molecular events involved in lymphatic development are poorly understood. Hence, the genes responsible for hereditary lymphedema are of great interest due to the potential for providing insights into the mechanisms of lymphatic development, the diagnosis, prevention and treatment of lymphedema, and lymphangiogenesis during tumor growth. Mutations in the FOXC2 transcription factor cause a major form of hereditary lymphedema, the lymphedema-distichiasis syndrome. We have conducted a study of Foxc2 expression during mouse development using immunohistochemistry, and examined its expression in lymphatics compared to its paralog Foxc1 and to Vegfr-3, Prox1 and other lymphatic and blood vascular proteins. We have found that Foxc2 is expressed in lymphatic primordia, jugular lymph sacs, lymphatic collectors and capillaries, as well as in podocytes, developing eyelids and other tissues associated with abnormalities in lymphedema-distichiasis syndrome.
Animals↗
Tamoxifen and vitamin E treatments delay symptoms in the mouse model of Niemann-Pick C.
Niemann-Pick C disease (NPC) is an irreversible neurodegenerative disorder without current treatment. It is the result of deficient intracellular cholesterol movement. We investigated the effects of tamoxifen and vitamin E (D-alpha tocopherol) treatment on patterns of weight loss and motor function in the mouse model of Niemann-Pick C disease (Npc1-/- mice). Tamoxifen has multiple metabolic effects, including reducing oxidative damage, while vitamin E primarily has this property. Npc1-/- mice were identified and treatment was initiated at an approximate age of 21 days. Tamoxifen suspended in peanut oil was administered via intraperitoneal injection (weekly, at a dose calculated to deliver 0.023 microg/g/day). Vitamin E (25 IU) was administered orally via gavage once a week. Weight loss and Rota-Rod performance were analyzed by using Kaplan-Meyer survival curves. Tamoxifen treatment by itself significantly delayed weight loss (an endpoint of neurodegeneration) in male and female mice compared to untreated controls. Motor function was evaluated by performance on a Rota-Rod. Tamoxifen maintained Rota-Rod performance for about an extra week. Vitamin E treatment significantly delayed weight loss in females only. Rota-Rod performance was maintained slightly longer in mice treated with vitamin E. Simultaneous use of both treatments did not delay weight loss longer than tamoxifen-only treatment but had a greater effect than either treatment alone on Rota-Rod performance and demonstrated a significant positive effect on the early "learning curve" portion of the Rota-Rod evaluations. We found significant but relatively small improvements in rate of disease progression by treating Npc1-/- mice with tamoxifen and/or vitamin E. Some sex differences in response and an early improvement in Rota-Rod performance suggest areas for further study.
Animals↗
Does chromosome 22 have anything to do with sex determination: further studies on a 46,XX,22q11.2 del male.
Several years ago, we presented a patient with true hermaphroditism and partial duplication of chromosome 22 and no evidence of SRY (Aleck et al. [1999: Am J Med Genet 85:2-4]). Recently a 46,XX male with velocardiofacial syndrome and a deletion of 22q11.2 and no evidence of Y chromosomal loci in blood DNA was reported (Phelan et al. [2003: Am J Med Genet 116A:77-79]). We have restudied this patient as he enters puberty. Because chromosomal deletions sometimes involve micro rearrangements of nearby material, we have extensively studied this individual's chromosome 22 looking for evidence of any gene duplication. We studied a number of variable number tandem repeat (VNTR) loci along chromosome 22 in the patient and both parents. Normal Mendelian inheritance of the VNTRs was found. We then used quantitative multiplex PCR of short fluorescent fragments (QMPSF) to delineate the 22q11.2 deletion in this patient (Jacquet et al. [2002: Hum Molec Genet 11:2243-2249]) and found a pattern of deletion typical of the velocardiofacial DiGeorge syndrome. Finally, the patient's DNA has been analyzed using a full coverage human chromosome 22 genomic microarray (array comparative genomic hybridization [CGH]) for evidence of rearrangements outside the classical velocardiofacial DiGeorge associated deletion (Buckley et al. [2002: Hum Molec Genet 11:3221-3229]). The array-CGH profile of this patient confirms the deletion encompassing the typically deleted region associated with the velocardiofacial DiGeorge syndrome and provides no support for additional gene copy number aberrations on 22q. Thus, there is no evidence of any chromosome 22 trisomic material. In this case, the rare events of sex reversal and 22q11.2 deletion may have occurred together by chance.
Chromosome Deletion↗
The effects of genetic variation in N-acetyltransferases on 4-aminobiphenyl genotoxicity in mouse liver.
Inbred, congenic and transgenic strains of mice were characterized for acetylation of p-aminobenzoic (PABA) and the carcinogen 4-aminobiphenyl (4ABP). C57Bl/6 mice have the NAT2*8 allele, A/J mice have NAT2*9 and congenic B6.A mice have NAT2*9 on the C57Bl/6 background. The first transgenic strain with human NAT1, the functional equivalent of murine NAT2, was also tested. The murine NAT2*9 allele correlated with a slow phenotype measured with the murine NAT2 selective substrate PABA. The two strains having this allele also had a lower capacity to acetylate 4ABP. A line with five copies of the human NAT1 transgene was bred for at least five generations with either C57Bl/6 or A/J mice. There was no significant change in PABA NAT activity on the C57Bl/6 background but a 2.5-fold increase was seen in hNAT1:A/J compared with A/J. The effect of variation in NATs on 4ABP genotoxicity was assessed in these strains. Twenty-four hours after exposure to a single oral dose of 120 mg 4ABP/kg, hepatic 4ABP-DNA adducts were detected by immunofluoresence in all strains. Nuclear fluorescence intensities (mean+/-S.D.) were 41.1+/-3.6 for C57Bl/6, 37.9+/-1.11 for A/J and 36.3+/-2.44 for B6.A. There was no correlation between murine NAT2 alleles and 4ABP-DNA adduct levels. Similar results were seen with the transgenic strains. The data indicate that the range of variation present in these strains of mice was insufficient to alter susceptibility to 4ABP genotoxicity. The impact of these relatively modest differences in the acetylation of the activation of 4ABP may be masked by other competing biotransformation reactions since 4ABP is a substrate for both NAT1 and NAT2. Mouse models with variation in both isoforms are needed to adequately assess the role of variation in NATs in susceptibility to 4ABP genotoxicity.
4-Aminobenzoic Acid↗
Athabascan brainstem dysgenesis syndrome.
We report a new disorder with diverse neurological problems resulting from abnormal brainstem function. Consistent features of this disorder, which we propose should be called the Atabascan brainstem dysgenesis syndrome, include horizontal gaze palsy, sensorineural deafness, central hypoventilation, and developmental delay. Other features seen in some patients include swallowing dysfunction, vocal cord paralysis, facial paresis, seizures, and cardiac outflow tract anomalies. All affected children described are of Athabascan Indian heritage, with eight children from the Navajo tribe and two patients who are of Apache background. The disorder can be distinguished from the Moebius syndrome by the pattern of central nervous system findings, especially the sensorineural deafness, horizontal gaze palsy, and central hypoventilation. Recognition of children with some features of Athabascan brainstem dysgenesis syndrome should prompt investigation for other related abnormalities. Published 2003 Wiley-Liss, Inc.
Abnormalities, Multiple↗
FOXC2 haploinsufficient mice are a model for human autosomal dominant lymphedema-distichiasis syndrome.
Lymphedema-distichiasis (LD) (OMIM 153400) is a rare autosomal-dominant condition characterized by pubertal onset of lower limb lymphedema and an aberrant second row of eyelashes arising from the meibomian glands. In some patients cardiac, skeletal and other defects coexist. We previously identified inactivating, nonsense and frameshift mutations in the forkhead transcription factor FOXC2 in affected members of LD families. To further delineate the relationship of FOXC2 deficiency to the clinical (and lymphangiodysplastic) phenotype in this syndrome, we performed dynamic lymphatic imaging and immunohistochemical examination of lymphatic tissues in mice heterozygous (+/-) for a targeted disruption of Foxc2. Adult heterozygote mice characteristically exhibited a generalized lymphatic vessel and lymph node hyper plasia and rarely exhibited hindlimb swelling. Retrograde lymph flow through apparently incompetent interlymphangion valves into the mesenteric nodes, intestinal wall and liver was also observed. In addition, Foxc2 +/- mice uniformly displayed distichiasis. We conclude that Foxc2 haploinsufficient mice mimic closely the distinctive lymphatic and ocular phenotype of LD patients. Furthermore, the craniofacial, cardiovascular and skeletal abnormalities sometimes associated with LD have previously been shown to be fully penetrant in homozygous Foxc2 null mice. This Foxc2 mutant mouse thus provides an ideal model for exploring molecular mechanisms and physiologic events in mesenchymal differentiation associated with lymphatic growth and development and the clinical abnormalities seen in human LD syndrome.
Animals↗
Association between osteosarcoma and deleterious mutations in the RECQL4 gene in Rothmund-Thomson syndrome.
BACKGROUND: Rothmund-Thomson syndrome (RTS) is an autosomal recessive disorder associated with an increased predisposition to osteosarcoma. Children with RTS typically present with a characteristic skin rash (poikiloderma), small stature, and skeletal dysplasias. Mutations in the RECQL4 gene, which encodes a RecQ DNA helicase, have been reported in a few RTS patients. We examined whether a predisposition to developing osteosarcoma among an international cohort of RTS patients was associated with a distinctive pattern of mutations in the RECQL4 gene. METHODS: We obtained clinical information about and biologic samples from 33 RTS patients (age range = 1-30 years). Eleven patients were diagnosed with osteosarcoma. All 21 exons and 13 short introns of the RECQL4 gene were sequenced from the genomic DNA of all subjects. Kaplan-Meier survival analysis was used to estimate the incidence of osteosarcoma among patients with and without mutations predicted to produce a truncated RECQL4 protein. RESULTS: Twenty-three RTS patients, including all 11 osteosarcoma patients, carried at least one of 19 truncating mutations in their RECQL4 genes. The incidence of osteosarcoma was 0.00 per year in truncating mutation-negative patients (100 person-years of observation) and 0.05 per year in truncating mutation-positive patients (230 person-years of observation) (P =.037; two-sided log-rank test). CONCLUSIONS: Mutations predicted to result in the loss of RECQL4 protein function occurred in approximately two-thirds of RTS patients and are associated with risk of osteosarcoma. Molecular diagnosis has the potential to identify those children with RTS who are at high risk of this cancer.
Adenosine Triphosphatases↗
Absence of RECQL4 mutations in poikiloderma with neutropenia in Navajo and non-Navajo patients.
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Adenosine Triphosphatases↗
Neuropeptides modulate rat chorda tympani responses.
The neuropeptide leptin has been shown to selectively modulate rat chorda tympani (CT) responses to sweet tastants. To explore whether other neuropeptides can modulate such responses, rat whole nerve CT responses to NaCl, HCl, quinine HCl, and sucrose were measured while administering cholecystokinin-8 (CCK-8), substance P(4-11) (SP(4-11)), or calcitonin gene-related peptide (CGRP). To avoid possible confounding effects on CT responses that take long times to develop, such as those that arise from intraperitoneal injections, we investigated the effects of the above peptides injected into the ipsilateral lingual artery (LA) on CT nerve responses during the initial seconds after a tastant was placed on the tongue. We found that CT responses to NaCl and HCl were increased by CCK-8 and decreased by CGRP. SP(4-11) had no noticeable effect. Peptide-induced CT responses to quinine HCl or sucrose were too small to accurately detect. These data suggest that at short latencies, after local infusion via the LA, neuropeptides can alter CT responses in a peptide-specific manner.
Animals↗