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Biomedical subjects

J J Higgins

Publications and source records attributed to J J Higgins.

At least 19 recordsLinked to original sources
PubMed2005

A variant in the HS1-BP3 gene is associated with familial essential tremor.

BACKGROUND: Genetic linkage studies have identified two susceptibility loci for essential tremor (ET) on chromosomes 3q13 (ETM1) and 2p24.1 (ETM2). Linkage disequilibrium studies in separate population samples from the United States and Singapore suggest an association between ET and loci at ETM2. METHODS: Fine mapping studies were conducted on multiplex and singleton US families linked to ETM2 using newly detected loci within the candidate interval to establish the minimal critical region (MCR) harboring an ET gene. The genes and transcripts within this interval were systematically analyzed by single-strand conformational polymorphism analysis and DNA sequencing. RESULTS: A 464-kb region between loci D2S2150 and etm1231 was defined as the MCR. The coding regions and flanking intronic splice sites of two genes and seven transcripts in this interval were evaluated for mutations. A missense mutation (828C-->G) in the transcript FLJ14249 (HS1-BP3) was identified in one US family. This mutation was found in another apparently unrelated US family with ET and was absent in 150 control samples (300 chromosomes). The 828C-->G mutation causes a substitution of a glycine for an alanine residue in the HS1-BP3 protein. The HS1-BP3 protein binds to proteins that are highly expressed in motor neurons and Purkinje cells and regulate the Ca2+/calmodulin-dependent protein kinase activation of tyrosine and tryptophan hydroxylase. CONCLUSIONS: A rare variant in the HS1-BP3 gene that is associated with essential tremor (ET) in two families is reported. This finding will facilitate research on the functional role of this gene and related genes in the pathogenesis of ET.

Adult↗
PubMed2005

Effects of L-carnitine on fetal growth and the IGF system in pigs.

The effects of L-carnitine on porcine fetal growth traits and the IGF system were determined. Fourth-parity sows were fed a gestation diet with either a 50-g top dress containing 0 (control, n = 6) or 100 mg of L-carnitine (n = 6). At midgestation, fetuses were removed for growth measurements, and porcine embryonic myoblasts (PEM) were isolated from semitendinosus. Real-time quantitative PCR was used to measure growth factor messenger RNA (mRNA) levels in the uterus, placenta, muscle, hepatic tissue, and cultured PEM. A treatment x day interaction (P = 0.02) was observed for maternal circulating total carnitine. Sows fed L-carnitine had a greater (P = 0.01) concentration of total carnitine at d 57 than control sows. Circulating IGF-I was not affected (P = 0.55) by treatment. Supplementing sows with L-carnitine resulted in larger (P = 0.02) litters (15.5 vs. 10.8 fetuses) without affecting litter weight (P = 0.07; 1,449.6 vs. 989.4 g) or individual fetal weight (P = 0.88) compared with controls. No treatment effect was found for muscle IGF-I (P = 0.36), IGF-II (P = 0.51), IGFBP-3 (P = 0.70), or IGFBP-5 (P = 0.51) mRNA abundance. The abundance of IGF-I (P = 0.72), IGF-II (P = 0.34), and IGFBP-3 (P = 0.99) in hepatic tissue was not influenced by treatment. Uterine IGF-I (P = 0.46), IGF-II (P = 0.40), IGFBP-3 (P = 0.29), and IGFBP-5 (P = 0.35) mRNA abundance did not differ between treatments. Placental IGF-I (P = 0.30), IGF-II (P = 0.18), IGFBP-3 (P = 0.94), and IGFBP-5 (P = 0.42) mRNA abundance did not differ between treatments. There was an effect of side of the uterus for IGF-I (P = 0.04) and IGF-II (P = 0.007) mRNA abundance; IGF-I mRNA abundance was greater in the left uterine horn than in the right uterine horn (0.14 and 0.07 relative units, respectively). Placental IGF-II mRNA abundance was greater (P = 0.007) in the left than in the right uterine horn (483.5 and 219.59, respectively). The abundance of IGFBP-3 was not affected by uterine horns in either uterine (P = 0.66) or placental (P = 0.13) tissue. There was no treatment difference for IGF-I (P = 0.31) or IGFBP-5 (P = 0.13) in PEM. The PEM isolated from sows fed L-carnitine had decreased IGF-II (P = 0.02), IGFBP-3 (P = 0.03), and myogenin (P = 0.04; 61, 59, and 67%, respectively) mRNA abundance compared with controls. These data suggest that L-carnitine supplemented to gestating sows altered the IGF system and may affect fetal growth and development.

Animals↗
PubMed2004

Candidate genes for recessive non-syndromic mental retardation on chromosome 3p (MRT2A).

A mild type of autosomal recessive, non-syndromic mental retardation (NSMR) is linked to loci on chromosome 3p. This report delimits the MRT2A minimal critical region to 4.2 Mb between loci D3S3630 and D3S1304. This interval contains nine genes (IL5RA, TRNT1, LRRN1, SETMAR, SUMF1, ITPR1, BHLHB2, EDEM, and MRPS36P1). The results suggest that a mutation does not exist in these genes and that an unknown transcript in the region contributes to the cognitive deficits in NSMR.

Chromosomes, Human, Pair 3↗
PubMed2004

Haplotype analysis at the ETM2 locus in a Singaporean sample with familial essential tremor.

An ancestral haplotype on chromosome 2p24.1 described in an American sample with familial essential tremor (ET) was analyzed in a different ethnic sample from Singapore. Six polymorphic loci (etm1240, etm1231, etm1234, APOB, etm1241, and etm1242) in a 274-kb interval within an ET gene candidate region (ETM2) were analyzed in Singaporean individuals with a family history of ET (n = 52) and compared to Singaporean controls older than age 65 (n = 49). The allele frequencies were significantly different between cases and controls for the loci etm1234 (p = 0.0001) and APOB (p = 0.0320). An extended haplotype formed by the loci etm1231, etm1234, and APOB occurred with a frequency of 31% in Singaporean cases and in 1.8% of elderly Singaporean controls (p = 0.0005). Haplotype studies in two different population samples suggest that a disease locus for ET lies near or within the 100-kb interval between the loci etm1231 and APOB.

Adolescent↗
PubMed2004

Effects of wet corn gluten feed and intake level on diet digestibility and ruminal passage rate in steers.

Twelve ruminally cannulated Jersey steers (BW = 534 kg) were used in an incomplete Latin square design experiment with a 2 x 2 factorial arrangement of treatments to determine the effects of wet corn gluten feed (WCGF) and total DMI level on diet digestibility and ruminal passage rate. Treatments consisted of diets formulated to contain (DM basis) steam-flaked corn, 20% coarsely ground alfalfa hay, and either 0 or 40% WCGF offered once daily for ad libitum consumption or limited to 1.6% of BW (DM basis). Two consecutive 24-d periods were used, each consisting of 18 d for adaptation, 4 d for collection, and a 2-d in situ period. Rumens of all steers were evacuated once daily at 0, 4, 8, and 12 h after feeding. Chromic oxide (10 g/[steer*d]) was fed as a digestibility marker, and steers were pulse-dosed with Yb-labeled alfalfa hay to measure ruminal particulate passage rate. Dacron bags containing 5 g of steam-flaked corn, WCGF, or ground (2-mm screen) alfalfa hay were placed into the rumens of all steers and removed after 3, 6, 12, or 48 h. Wet corn gluten feed increased percent apparent total-tract digestion of OM (P < 0.01), NDF (P < 0.01), and starch (P < 0.03), decreased (P < 0.01) ruminal total VFA concentration, increased (P < 0.01) ruminal NH3 concentration, and increased (P < 0.01) ruminal pH. Wet corn gluten feed also increased (P < 0.01) ruminal passage rate of Yb. Limit feeding decreased (P < 0.01) percent apparent total-tract digestion of both OM and NDF, ruminal total VFA concentration (P < 0.01), and ruminal fill (P < 0.01), but increased (P < 0.01) ruminal NH3 concentration. Apparent total-tract digestion of starch was not affected (P = 0.70) by level of DMI. A DMI level x hour interaction (P < 0.01) occurred for ruminal pH. Limit feeding increased ruminal pH before and 12 h after feeding, but decreased ruminal pH 4 h after feeding compared with diets offered ad libitum. A diet x DMI level interaction (P < 0.02) occurred for in situ degradation of alfalfa hay, with dietary addition of WCGF increasing (P < 0.02) the extent of in situ alfalfa hay degradation in steers fed for ad libitum consumption. This study suggests that WCGF increases OM and NDF digestion, and that limit feeding diets once daily might depress OM and NDF digestion, possibly due to decreased stability of the ruminal environment.

Animal Feed↗
PubMed2003

Wet corn gluten feed and alfalfa hay combinations in steam-flaked corn finishing cattle diets.

One finishing trial and one digestibility trial were used to evaluate wet corn gluten feed (WCGF) and alfalfa hay (AH) combinations in steam-flaked corn (SFC) finishing diets. In Exp. 1, 631 crossbred heifers (initial BW = 284 +/- 7.9 kg) were fed SFC-based diets containing combinations of WCGF (25, 35, or 45% of diet DM) and AH (2 or 6% of dietary DM) in a 2 x 3 factorial arrangement of treatments. No interactions existed between WCGF and AH for heifer performance. Increasing dietary WCGF linearly decreased gain efficiency (P < 0.01), dietary NEg concentration (P < 0.05), and 12th-rib fat thickness (P = 0.10). Cattle fed 35% WCGF had the lowest occurrence of abscessed livers, resulting in a quadratic response (P < 0.05) as dietary WCGF increased. In Exp. 2, 12 ruminally cannulated Jersey steers (585 kg) were fed SFC-based diets containing combinations of WCGF (25 or 45% of diet DM) and AH (0, 2, or 6% of diet DM) in an incomplete Latin square design with a 2 x 3 factorial arrangement of treatments. Starch intake was lower (P < 0.05), but NDF intake was greater (P < 0.05) as AH and WCGF increased in the diet. Ruminal pH was increased by AH (linear, P < 0.05) and tended (P < 0.07) to increase with WCGF. Feeding 2% AH led to the greatest ruminal NH3 but the lowest total VFA and propionate (quadratic, P < 0.05). Addition of AH to diets containing 25% WCGF increased acetate to a greater extent than addition to diets containing 45% WCGF (AH x WCGF interaction, P < 0.05). Feeding 45% WCGF tended to increase passage rate (P = 0.17) and decrease (P < 0.05) total tract OM digestibility but increase (P < 0.05) in situ degradation of DM from AH and WCGF. Interactions between AH and WCGF existed (P < 0.05) for ruminal fluid volume (quadratic effect of AH x WCGF level), in situ SFC degradation (linear effect of AH x WCGF level), and in situ rate of WCGF DM disappearance (quadratic effect of AH x WCGF level). We conclude that AH levels may be decreased when WCGF is added to SFC diets as 25% or more of the dietary DM.

Animal Feed↗
PubMed2002

HARP syndrome is allelic with pantothenate kinase-associated neurodegeneration.

HARP (hypoprebetalipoproteinemia, acanthocytosis, retinitis pigmentosa, and pallidal degeneration) is a rare syndrome with many clinical similarities to pantothenate kinase-associated neurodegeneration (PKAN, formerly Hallervorden-Spatz syndrome). Despite these common features, lipoprotein abnormalities have not been reported in PKAN. After the recent discovery of the genetic defect in PKAN, we report a homozygous nonsense mutation in exon 5 of the PANK2 gene that creates a stop codon at amino acid 371 (R371X) in the original HARP patient. This finding establishes that HARP is part of the PKAN disease spectrum.

Acanthocytes↗
PubMed2002

Evaluation of finishing performance, carcass characteristics, acid-resistant E. coli and total coliforms from steers fed combinations of wet corn gluten feed and steam-flaked corn.

Crossbred beef steers (n = 615) were used in a 152-d experiment to compare steam-flaked corn (SFC) diets containing 0, 30, or 60% wet corn gluten feed (WCGF). On d 114 to 118, ruminal and fecal samples were collected from 180 steers and analyzed for pH, VFA, and total and acid-resistant Escherichia coli and coliforms. Acid resistance of E. coli and coliform populations was determined by exposure of the samples for 1 h in pH 2, 4, and 7 citric acid/sodium phosphate buffers. Increasing levels of WCGF linearly decreased total ruminal VFA (P = 0.01) and total fecal VFA (P = 0.06), but linearly increased ruminal and fecal acetate:propionate (P < 0.01) ratio and ruminal and fecal pH (P < 0.05). Feeding increasing WCGF levels resulted in a quadratic response (P < 0.05) with respect to numbers of ruminal E. coli and total coliform populations resistant to pH 4 exposure. Steers fed 30% WCGF had higher (0.7 log units) ruminal E. coli and total coliforms after exposure at pH 4 compared to steers fed 0 or 60% WCGF. Populations of E. coli and total coliforms at pH 2 and 7 were similar for all dietary treatments. Dietary WCGF linearly increased DMI (P = 0.07) and liver abscesses (P = 0.03) and linearly decreased dietary NEg (P = 0.02). Average daily gain and feed efficiencies were greatest when steers were offered 30% WCGF (quadratic, P < 0.05). Dietary manipulations that reduce acid concentrations may not correspond to changes in acid resistance of E. coli and total coliform populations detected in the gastrointestinal tracts of cattle. Moderate levels of WCGF complement SFC finishing diets.

Animal Feed↗
PubMed2002

Effects of a Quillaja saponaria extract on growth performance and immune function of weanling pigs challenged with Salmonella typhimurium.

Ninety-six pigs (initially 8.9 kg and 24 d of age) were used in a 28-d experiment to determine the effects of Quillaja saponaria extract (QS) on weanling pig growth performance and immune function in response to enteric disease challenge with Salmonella typhimurium (ST). Experimental treatments were arranged in a 2 x 4 factorial with main effects of disease challenge (control vs ST-challenge) and dietary addition of QS (0, 125, 250, or 500 mg/kg). Pigs were fed QS diets for 14 d and then challenged orally with ST or sterile media. There were no differences in ADG or ADFI among dietary treatments, but gain/feed ratio (G/ F) was depressed (P < 0.06) in pigs fed 250 mg/kg QS. ST-challenge reduced ADG (P < 0.05), ADFI (P < 0.05), and G/F (P < 0.05) 1 wk after challenge. Daily estimates revealed reductions in feed intake in ST-infected pigs on d 2 to 5 following infection (P < 0.05), and rectal temperature was increased maximally 2 d following infection (P < 0.05). There was a marked decline in serum IGF-I during the 6 d after ST-infection (P < 0.05). ST-challenge produced a rise (P < 0.05) in serum haptoglobin on d 7 after challenge, and serum alpha1-acid glycoprotein (AGP) in ST-challenged pigs also was elevated (P < 0.05) above controls on d 7 and 14 after challenge. Serum immunoglobulin (Ig) M increased (P < 0.05) over time in both groups, and serum IgM of ST-challenged pigs was greater than controls on d 7 after challenge (P < 0.05). Serum IgG was not affected by enteric disease challenge; however, on d 7 and 14 after disease challenge, serum IgG for both groups was greater (P < 0.05) than on d 0. Dietary QS had no significant influence on any of the end points used to characterize the acute phase response to ST-challenge. Phagocytic cell function was depressed in pigs fed 250 (P < 0.05) and 500 (P < 0.05) mg/kg as compared to pigs fed 125 mg/kg QS. Yet, there was no difference in phagocytic function among pigs fed 0, 250, or 500 mg/kg QS. We conclude that this model of enteric disease invokes an acute phase response accompanied by decreases in feed intake and serum IGF-I. Furthermore, dietary QS, at the levels fed in this study, appears to offer little benefit to growth performance or immune function in the presence or absence of ST-challenge.

Acute-Phase Proteins↗
PubMed2002

Effects of Ascophyllum nodosum extract on growth performance and immune function of young pigs challenged with Salmonella typhimurium.

Ninety-five pigs (initially 7.1 kg and 24 d of age) were used in a 28-d experiment to determine the effects of Ascophyllum nodosum seaweed extract (ANOD) on young pig growth performance and immune function in response to enteric disease challenge with Salmonella typhimurium (ST). Experimental treatments were arranged in a 2 x 4 factorial with main effects of disease challenge (control vs ST-challenge) and dietary addition of ANOD (0, 0.5, 1.0, and 2.0% of diet). Pigs were fed ANOD diets for 14 d and then challenged orally with ST or sterile media. There were no main effects of ANOD on growth performance end points, although there were significant quadratic effects of ANOD on ADG (P < 0.04) and final weight (P < 0.003), both being greatest at 1.0% ANOD. There was a positive linear effect of ANOD inclusion on ADFI (P < 0.07) and a negative linear effect on the gain-to-feed ratio (G/F) (P < 0.05). ST-challenge reduced ADG (P < 0.05), ADFI (P < 0.05), and G/F (P < 0.05) in the first week following challenge. Daily estimates revealed reductions in feed intake in ST-infected pigs on d 2 to 4 following infection (P < 0.05). Rectal temperature was increased maximally 2 d following ST-infection (P < 0.05). A disease challenge x time interaction (P < 0.001) was observed for serum haptoglobin and alpha1-acid glycoprotein. Serum immunoglobulin M (IgM) was not influenced by disease challenge, but IgM declined (P < 0.001) in all pigs over time. Serum immunoglobulin G (IgG) also was not influenced by disease challenge, but IgG tended (P < 0.08) to increase over time. In vitro culture of porcine alveolar macrophages with 10 mg/mL ANOD elevated (P < 0.05) prostaglandin E2 (PGE2) production over that of controls at 3 and 24 h of culture. There was no interleukin-10 response by porcine splenocytes cultured in vitro with 0.005, 0.05, 0.5, or 5 mg/mL ANOD. We conclude that this model of enteric disease elicits an acute phase response that is accompanied by increased rectal temperature and diminished feed intake. Furthermore, our results indicate some beneficial effects of dietary ANOD on growth performance and no influence of dietary ANOD on immune response in the presence or absence of ST-challenge. However, high ANOD concentrations are capable of activating porcine alveolar macrophages in vitro to secrete PGE2.

Acute-Phase Proteins↗
PubMed2001

An atypical intronic deletion widens the spectrum of mutations in hereditary spastic paraplegia.

OBJECTIVE: To identify the genetic mutation responsible for autosomal dominant spastic paraplegia (HSP) in a large family with a "pure" form of the disorder. BACKGROUND: The disease locus in most families with HSP is genetically linked to the SPG4 locus on chromosome 2p21-p22. Some of these families have mutations in the splice-site or coding regions of the spastin gene (SPAST). METHODS: Linkage and mutational analyses were used to identify the location and the nature of the genetic defect causing the disorder in a large family. After the disease phenotype was linked to the SPG4 locus, all 17 coding regions and flanking intronic sequences of SPAST were analyzed by single-strand conformation polymorphism analysis (SSCP) and compared between affected and normal individuals. Direct sequencing and subcloning methods were used to investigate incongruous mobility shifts. RESULTS: The genomic sequence of SPAST showed a heterozygous four--base pair deletion (delTAAT) near the 3' splice-site of exon three in all 11 affected individuals but not in 21 normal family members or in 50 unrelated controls (100 chromosomes). CONCLUSIONS: This study identifies an atypical intronic microdeletion in SPAST that causes HSP and widens the spectrum of genetic abnormalities that cause the disorder.

Adult↗
PubMed2001

Effect of ruminal vs postruminal administration of degradable protein on utilization of low-quality forage by beef steers.

An experiment was designed to determine the effects of ruminal and postruminal infusions of ruminally degradable protein (casein) on intake and digestion of low-quality hay by beef steers. Twelve ruminally fistulated Angus x Hereford steers (initial BW = 563 kg) were blocked by weight and assigned to one of three treatments: control (C; hay only) or hay plus ruminal (R) or postruminal (P) infusion of 400 g/d of sodium caseinate. The trial consisted of five periods: 1) 10-d adaptation to the hay diet; 2) 7-d measurement of hay intake (without infusions); 3) 10-d adaptation to protein infusion treatments (intake measurements continued); 4) 7-d measurement of hay intake and digestibility (infusions continued); and 5) 3-d ruminal sampling period (infusions continued). Steers were given ad libitum access to tallgrass-prairie hay (3.4% CP, 76.6% NDF) throughout the study. Casein was administered once daily before feeding, either directly into the rumen or via anchored infusion lines into the abomasum. Hay intake was increased by supplementation (P < 0.01). Ruminal infusion elicited a greater (P = 0.04) increase in hay intake than postruminal infusion. Intake tended (P = 0.11) to be lower in period 4 than in period 2 for control steers but was greater in period 4 than in period 2 (P < or = 0.03) for both R and P steers. The increase in intake between periods 2 and 4 was greater for R than for P steers (P = 0.03). Supplementation improved diet OM digestion (P = 0.04) but not NDF digestion (P = 0.18); however, greater relative error for NDF digestion may have limited the ability to elucidate significant treatment effects. There were no differences in either OM digestion (P = 0.42) or NDF digestion (P = 0.35) between R and P steers. Plasma urea N at 0 and 3 h after feeding on the last day of the experiment was lower (P = 0.05) for C than for R and P steers, but no difference (P = 0.48) was evident between R and P steers. Ruminal ammonia N levels also were increased by supplementation (P < 0.01), with a much larger increase for R than for P steers (P < 0.01). Total VFA concentrations were not affected (P = 0.21) by treatment, but R steers exhibited lower proportions of acetate and higher proportions of isobutyrate, valerate, and isovalerate than P steers (P < 0.01). In conclusion, ruminal and postruminal infusion of a degradable protein source improved forage utilization, although the response in forage OM intake and total digestible OM intake was greater for ruminal infusion than for postruminal infusion.

Animal Feed↗
PubMed2000

Ancestral origins of the Machado-Joseph disease mutation: a worldwide haplotype study.

Machado-Joseph disease (MJD) is an autosomal dominant neurodegenerative disorder originally described in families of Portuguese-Azorean ancestry. The cloning of the MJD1 gene allowed identification of the disease in many other populations, and MJD is now known to be the most common cause of dominant spinocerebellar ataxia. The hypothesis that its present world distribution could result from the spread of an original founder mutation has been raised, both at historical and molecular levels. In the present study, we tested this hypothesis by linkage-disequilibrium analysis of tightly linked polymorphisms and by haplotype comparison, in 249 families from different countries. We typed five microsatellite markers surrounding the MJD1 locus (D14S1015, D14S995, D14S973, D14S1016, and D14S977), and three intragenic single-base-pair polymorphisms (A(669)TG/G(669)TG, C(987)GG/G(987)GG, and TAA(1118)/TAC(1118)). The results show two different haplotypes, specific to the island of origin, in families of Azorean extraction. In families from mainland Portugal, both Azorean haplotypes can be found. The majority of the non-Portuguese families also share the same intragenic haplotype seen in the families coming from the island of Flores, but at least three other haplotypes were seen. These findings suggest two introductions of the mutation into the Portuguese population. Worldwide, the sharing of one intragenic haplotype by the majority of the families studied implies a founder mutation in MJD.

Alleles↗
PubMed2000

An extended 5'-tau susceptibility haplotype in progressive supranuclear palsy.

OBJECTIVE: To confirm the association of an extended 5'-tau haplotype on chromosome 17q with the disease phenotype in clinically ascertained individuals with sporadic progressive supranuclear palsy (PSP). BACKGROUND: PSP is a neurodegenerative disease with parkinsonian signs accompanied by vertical supranuclear palsy and tau pathologic features. Previously, we documented the complete segregation of an extended 5'-tau haplotype consisting of four single nucleotide polymorphisms (SNP) with the disease phenotype in sporadic PSP. This study was conducted in an independent cohort to confirm these results and to improve the statistical power of the data. DESIGN AND METHODS: Direct sequencing and restriction enzyme digests were used to analyze four SNP in tau Exons 1, 4A, and 8. These contiguous SNP were used to reconstruct an extended 5'-tau haplotype in 52 affected and 54 age-matched control individuals. RESULTS: The four SNP formed two homozygous 5'-tau haplotypes (HapA and HapC) or a heterozygous genotype. Fifty-one (98%) patients with PSP had HapA; one (2%) with a later onset was heterozygous; and none had HapC. These PSP haplotype frequencies were different (p < 0.00001) from those of the age-matched control group, in which 18 (33%) people had HapA; 26 (48%) were heterozygous; and 10 (19%) had HapC. The extended 5'-tau haplotype, HapA, had a high sensitivity (98%) and a moderate specificity (67%) as a marker for PSP. CONCLUSIONS: A 5'-tau susceptibility haplotype may be a sensitive marker for sporadic PSP and a genetic defect in, or closely linked to, tau may contribute to the cause of PSP.

Chromosomes, Human, Pair 17↗
PubMed2000

A gene for nonsyndromic mental retardation maps to chromosome 3p25-pter.

OBJECTIVE: To establish genetic linkage between polymorphic microsatellite loci and a disease locus responsible for an autosomal recessive type of nonsyndromic mental retardation (MR). BACKGROUND: Although MR is the most common developmental disability in the United States, the etiologies of most nonsyndromic cases are not known. METHODS: A genealogic database provided information to reconstruct the relationships between 32 individuals from five nuclear families in a single pedigree with 10 affected individuals with nonsyndromic MR. To find a MR disease locus in this population, we performed a genome-wide search using genetic loci spaced at 10- to 20-cM intervals. Pairwise linkage analysis, multipoint linkage analysis, and haplotype reconstruction were used to localize the disease gene. RESULTS: Genetic linkage between a MR disease locus and locus D3S3050 on chromosome 3p25-pter was established with a Zmax = 9.18 at theta = 0.00. Fine mapping this region delimited a 13. 47-cM candidate interval defined by key recombinants at loci D3S3525 and D3S1304. Multipoint linkage analysis refined the critical region to a 6.71-cM interval flanked by loci D3S3525 and D3S1560. Evidence that a gene for MR resides in this location is supported by previous breakpoint deletion mapping studies performed in the chromosome 3p- syndrome. CONCLUSIONS: These results suggest that a gene on the subtelomeric region of chromosome 3p contributes to general intelligence. The genes for the cell adhesion L1-like molecule (CALL), the inositol triphosphate receptor (ITPR1), and the AD neuronal thread protein (AD7c-NTP) are leading positional candidates because of their role in brain development, neuronal signaling, and structure.

Adult↗
PubMed2000

Posterior column ataxia and retinitis pigmentosa: a distinct clinical and genetic disorder.

Autosomal recessive posterior column ataxia and retinitis pigmentosa (PCARP) is a movement disorder that was genetically mapped to a disease locus (AXPC1) on chromosome 1q32-q31 in an inbred population of Dutch-German ancestry in the continental United States. We performed genetic linkage analysis and haplotype reconstruction on a different family from Spain with an identical phenotype to determine if the neurologic signs of an early-onset ataxia, retinitis pigmentosa, and a sensory neuropathy also mapped to the AXPC1 locus. The disease phenotype was linked in the candidate interval with a maximum lod score of 3.56 at a recombination fraction of 0.0 for locus D1S414. Haplotypes were discordant and suggested that the disease mutation arose independently from at least two populations. These results refine the classification of early-onset ataxia, abrogate a founder effect for this recessive disorder, and provide evidence that PCARP is a distinct, homogeneous, clinical, and genetic disorder.

Child↗
PubMed1999

Mutational analysis of the tau gene in progressive supranuclear palsy.

OBJECTIVE: To identify genetic mutations in the coding regions and the splice-donor sites of the tau gene on chromosome 17q in individuals with progressive supranuclear palsy (PSP). BACKGROUND: Several studies provide evidence for linkage disequilibrium between a PSP disease gene and allelic variants of the tau gene. However, a causative mutation has not been identified. METHODS: We designed a study to search for genetic mutations in 15 coding regions of the tau gene including the splice-donor sites in 22 patients with PSP by comparing the mobility shifts on single-strand conformation analysis with those of age-matched controls. Fragments with altered migration were sequenced directly and compared for differences in nucleotide composition. Restriction enzyme digests were used to confirm single base-pair substitutions. RESULTS: Significant differences in mobility shifts were found in exons 1, 4A, and 8 between affected individuals and age-matched controls. All individuals with PSP had a common extended haplotype characterized by a homozygous polymorphism in the 5' splice site untranslated region of exon 1, two missense mutations in exon 4A (Asp285Asn, Ala289Val), and a nonsense mutation in the 5' splice site of exon 8. CONCLUSIONS: This study demonstrates that 22 unrelated progressive supranuclear palsy (PSP) patients have four identical sequence variants within the tau gene that are not present in 24 age-matched controls. Although the functional significance of these results on tau protein expression is unknown, the presence of this "susceptibility" haplotype in individuals may place them at risk for developing PSP.

Aged↗