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R H McLean

Publications and source records attributed to R H McLean.

At least 37 records · Page 2Linked to original sources
PubMed1990

Connective tissue disease in southeast Georgia. A community based study of immunogenetic markers and autoantibodies.

HLA antigens, C4 allotypes and T cell antigen receptor (TcR)beta DNA polymorphisms were determined in a community based study of connective tissue diseases (CTD). HLA-B8, DR3 and C4A null phenotypes occurred frequently in Caucasian patients with CTD, especially those with systemic lupus erythematosus (SLE), but were also more commonly found among healthy white controls of this southeast Georgia community. TcR beta gene polymorphisms also showed differential segregation patterns between patients with SLE and scleroderma. High frequencies of ANA and anti-ssDNA antibodies occurred among apparently healthy family members and local controls. Genetic factors predisposing to CTD in a community setting appear to be similar to those reported from referral centers.

Alleles↗
PubMed1989

Association of homozygous C4B deficiency with bacterial meningitis.

The fourth component of complement (C4) is encoded by two separate but linked loci (C4A and C4B), each of which produces functionally active C4. Although C4A and C4B share certain antigenic and functional characteristics that identify them as C4, they differ with respect to other structural and functional properties. For example, C4B possesses four times the functional hemolytic activity of C4A. This suggests that homozygous deficiency of C4B might be associated with an increased susceptibility to infection. Forty-six children with bacterial meningitis were examined. Of these, 5 (10.9%) were homozygous deficient for C4B versus 7 (3.1%) of 223 controls (P = 0.038). There was no relation between the prevalence of heterozygous C4B deficiency and meningitis or between the prevalence of either homozygous or heterozygous C4A deficiency and meningitis. These results suggest that homozygous C4B deficiency is a relatively common immunodeficiency disorder that is clinically significant and predisposes children to bacterial meningitis.

Adolescent↗
PubMed1988

Molecular heterogeneity of complement component C4-null and 21-hydroxylase genes in systemic lupus erythematosus.

C4A-null alleles (C4A*Q0) and hereditary complete C4 deficiency (homozygous C4A*Q0,C4B*Q0) are associated with systemic lupus erythematosus (SLE). Using Southern blot analysis with C4 and 21-hydroxylase (21-OH) DNA probes, we studied SLE patients and normal control subjects with or without C4A*Q0, and 2 C4-deficient SLE patients. A previously reported large C4A,21-OHA gene deletion associated in normal subjects with the HLA-A1;B8;DR3;C4AQ0 haplotype was detected by the appearance of a new C4 Hind III 8.5-kb fragment and disappearance of a 3.2-kb 21-OH Taq I fragment. In 3 SLE patients with homozygous C4A*Q0 and 15 with heterozygous C4A*Q0, this deletion pattern occurred almost exclusively in association with the HLA-B8;DR3;C4A*Q0 phenotype; the one exception was a black SLE patient. Other C4A*Q0-bearing HLA phenotypes in white patients and black patients with SLE, and the 2 completely C4-deficient SLE patients, had normal DNA hybridization to both C4 and 21-OH probes. The genetic basis for C4-null alleles in SLE is heterogeneous. A large C4A,21-OHA deletion occurs mainly on the HLA-B8;DR3;C4AQ0 haplotype in SLE and controls. Other HLA haplotypes bearing C4A*Q0 have normal C4 and 21-OH genes, as demonstrated by Southern blot analysis.

Alleles↗
PubMed1988

Neonatal obstructive uropathy.

Neonatal obstructive uropathy is the leading cause of renal failure during infancy. A variety of upper and lower genito-urinary (GU) tract disorders may cause obstructive uropathy. The prompt diagnosis and evaluation of obstructive uropathy is imperative since appropriate intervention and follow-up can lead to excellent early recovery of function. The role of in utero diagnosis is primarily to alert physicians to the presence of obstructive uropathy and permit rapid initiation of care at birth or earlier in certain instances. The GU tract must be evaluated for evidence of dilatation, for reflux and for renal function using radionuclide studies, voiding cystourethrograms, cystoscopy and pyelography. The early course of neonatal obstructive uropathy has been improved by institution of GU diversion and primary repair, yet the effect of early surgical intervention and medical therapy in preventing renal failure remains unclear. Further studies are needed to identify prognostic features heralding progression to renal failure and how such progression can be prevented.

Female↗
PubMed1988

Restriction fragment analysis of duplication of the fourth component of complement (C4A).

The two genes encoding the fourth component of complement (C4A and C4B) reside between HLA-B and HLA-DR on human chromosome 6. Two kilobases downstream from each C4 gene lies a 21-hydroxylase gene (CA21HA and CA21HB, respectively). Utilizing the method of Southern blotting and a 5'-end 2.4-kb BamHI/KpnI fragment of the C4 cDNA, we have analyzed TaqI-digested DNA from four pedigrees with one or more extended haplotypes containing a C4A duplication, as demonstrated by protein electrophoresis and segregation analysis. Two C4A protein duplications (C4A*2,A*3,C4B*QO and C4A*3,A*5,C4B*QO) segregated with two large TaqI DNA restriction fragments (7.0 and 6.0). In pedigree Fi, one individual homozygous for HLA-A3,B35,C4,DR1,DQ1,BFF,C2C,-C4A2,3,C4BQO had TaqI 7.0- and 6.0-kb restriction fragments with equal hybridization intensities as measured by two-dimensional densitometry (7.0/6.0 kb = 0.83, SD = 0.12, N = 7). A hybridization probe for the 21-hydroxylase gene also demonstrated equal gene dosage (CA21HA/CA21HB = 1.01). DNA from another individual (Ma I-2) with a different C4A gene duplication (C4A*3,A*5,C4B*QO) also had equal densitometry measurements (7.0/6.0 kb = 1.07). We conclude that two extended haplotypes from unrelated pedigrees have two C4 genes and both C4 genes encode separate C4A alleles. These findings are compatible with a gene conversion event of C4B to C4A.

Adrenal Hyperplasia, Congenital↗
PubMed1987

Prevalence of polymorphic 21-hydroxylase gene (CA21HB) mutations in salt-losing congenital adrenal hyperplasia.

Using genomic restriction analysis of 14 unrelated patients with salt-losing congenital adrenal hyperplasia, we identified three different CA21HB mutation patterns: no detectable restriction fragment abnormalities (16/28 haplotypes), deletion of the active CA21HB gene (9/28), and apparent conversion of the active CA21HB gene to the pseudogene CA21HA (3/28). CA21HB gene deletion was associated with HLA-Bw47 in 6 haplotypes and with absent C4B expression in 7. A variety of HLA and C4 types was associated with the other mutations. Apparent conversion of CA21HB to CA21HA was identified by the disparity between the intensity ratios for the major TaqI and BglII hybridization fragments.

Adrenal Hyperplasia, Congenital↗
PubMed1987

Hereditary partial deficiency of the third component of complement associated with minimal change nephrotic syndrome.

We describe a 10 year old patient admitted to the Children's Hospital of Buffalo with hypocomplementemia associated with steroid responsive minimal change nephrotic syndrome. The sibling also had a low serum C3 concentration and all family members studied had C3 slow phenotypes. Factor I levels were at the lower limit of normal in the patient and his brother. Functional assays for CH50, total hemolytic C3 and serum concentration of C2, C4-C9 and factors B and H were all within normal limits. This case confirms that a depressed serum complement level can occur in minimal change nephrotic syndrome and indicates that this depression could represent a preexisting inherited rather than an acquired deficiency. The findings are consistent with the presence of a null or hypomorphic C3 slow allele in hypocomplementemic family members. Additional studies are needed to resolve the association between the inherited partial C3 deficiency and minimal change nephrotic syndrome.

Child↗
PubMed1987

Serositis with autoimmune endocrinopathy: clinical and immunogenetic features.

Twenty patients with autoimmune endocrinopathies experienced 45 episodes of pleural and/or pericardial serositis. Seventeen of these patients were women and 15 had clinical or serologic evidence of 2 or more endocrinopathies. Idiopathic primary hypoadrenalism (10 cases), Graves' disease (8 cases), Hashimoto's disease (4 cases), atrophic thyroiditis with hypothyroidism (3 cases), idiopathic primary hypogonadism (3 cases), transient thyroiditides (2 cases), and type I diabetes mellitus (1 case) were diagnosed at a mean age of 24 years. Serositis recurred after asymptomatic intervals of months to years even in patients treated for endocrine dysfunction. Fourteen of 16 Caucasians had circulating immune complexes, including all 9 patients with a C4AQ0 (C4A null) phenotype and including all 12 patients with HLA antigens B8 and DR3, antigens associated with systemic lupus and with autoimmune endocrinopathies. Serositides associated with autoimmune endocrinopathies can occur with chest pain, fever, and exudative effusions in young Caucasian women with the HLA B8 DR3 C4AQ0 phenotype. These serositides may have a common pathophysiologic mechanism.

Adolescent↗
PubMed1987

Coupling of HLA-A3,Cw6,Bw47,DR7 and a normal CA21HB steroid 21-hydroxylase gene in the Old Order Amish.

HLA-Bw47, a rare human histocompatibility antigen, occurs in strong linkage disequilibrium with HLA-A3,Cw6,DR7 and salt-losing congenital adrenal hyperplasia (CAH) due to 21-hydroxylase deficiency and is associated with a contiguous deletion of the active CA21HB gene and the C4B complement gene. We studied the HLA-A3,Cw6,Bw47,DR7 haplotype in 10 subjects of the Old Order Amish of Lancaster County in Pennsylvania and found that this haplotype, which occurs with a similar frequency in this group as in the general caucasoid population, has C4B and Ca21HB genes. These C4B and CA21HB genes are expressed as assessed by C4 typing and iv ACTH testing, respectively. Serological studies indicate that the HLA-D loci of this Amish haplotype are the same as those in patients with HLA-Bw47 and CAH, but different from HLA-D loci coupled to HLA-B13, which some workers have proposed is the progenitor genotype for HLA-Bw47. Our studies demonstrate that 1) HLA-Bw47 is not an invariant marker for salt-losing CAH due to 21-hydroxylase deficiency, and 2) the HLA-Bw47 phenotype coupled to CAH is not derived from the HLA-B13 genotype by a single mutation.

Adrenal Hyperplasia, Congenital↗
PubMed1987

Systemic sclerosis (scleroderma): clinical, genetic, and serologic subsets.

Immunogenetic markers, autoantibodies, and clinical features were studied in 47 patients, 35 Caucasian and 12 black, with systemic sclerosis. Twenty-two had generalized scleroderma, while 25 had limited skin involvement. HLA-DR1 (RR = 2.1, p = 0.08) and DR5 (RR = 2.1, p = 0.08) were increased in Caucasian patients vs controls as was the supertypic specificity HLA-DRw52 (RR = 2.8, p = 0.02, pc = 0.04). HLA-DR6.1 was increased in black patients vs controls (RR = 15.4, p = 0.008, pc = 0.088). There were no significant increases in any of the complement allotypes in either racial group. Anticentromere antibody was noted in 10 patients, all Caucasian; 7 had limited disease. Anti-Scl-70 was noted in 4 patients; all had generalized disease (p = 0.036). HLA-DR2 was present in all anti-Scl-70 positive patients (RR = 22.5, p = 0.006). Our results suggest that clinical subsets of systemic sclerosis can be defined by genetic and serological markers.

Adult↗
PubMed1986

Restriction maps and restriction fragment length polymorphisms of the human 21-hydroxylase genes.

Restriction maps were constructed for the two human 21-hydroxylase genes (21-OHA and 21-OHB) by using DNA from subjects homozygous for a deletion of each gene. Comparing the patterns of these two genes, a KpnI restriction site occurred in the 21-OHA gene in place of a TaqI site in the 21-OHB gene about 1-kb from the 5' end of the gene, and an extra EcoRI site was located 500 bp 5' to the common EcoRI site. The DNA of fourteen unrelated normal subjects was digested with nine restriction endonucleases (AccI, BamHI, BgIII, EcoRI, HindIII, KpnI, MspI, SacI and TaqI). Restriction fragment length polymorphisms were found with EcoRI, HindIII and AccI that resulted from polymorphic endonuclease sites outside the genes.

Adrenal Hyperplasia, Congenital↗
PubMed1986

Genetic analysis of an inherited deficiency of the third component of complement in Brittany spaniel dogs.

Genetically determined C3 deficiency in Brittany spaniel dogs shares a number of biochemical and clinical characteristics with the human disorder. In humans, the gene for C3 deficiency is a null gene that is allelic to the structural gene for C3 and is not linked to the major histocompatibility locus. The current study used allotype analysis of canine C3 in order to demonstrate that the gene for C3 deficiency in these dogs is also a null gene allelic to the structural gene for C3. In addition, preliminary pedigree analysis suggests that the gene for canine C3 deficiency is apparently not closely linked to the major histocompatibility complex of the dog. Thus, it appears that C3 deficiency in Brittany spaniel dogs not only shares biochemical and clinical features with C3 deficiency in humans, but also shares some genetic characteristics with the human disorder.

Alleles↗
PubMed1986

Relationship between C4 null genes, HLA-D region antigens, and genetic susceptibility to systemic lupus erythematosus in Caucasian and black Americans.

The complement components C4A, C4B, and factor B, and the HLA-A, B, C, DR, DQ, and DRw antigens were analyzed in 103 patients (66 Caucasian, 37 black) with systemic lupus erythematosus (SLE) and 98 control subjects (63 Caucasian, 35 black). Only the C4A null (silent) allele was significantly increased in SLE (0.254 versus 0.095 in Caucasians, p = 0.033; 0.200 versus 0.071 in blacks, p = 0.046). The absence of any detectable C4A gene products (homozygous C4A null or C4A*Q0,Q0) was found in 11.1 percent of Caucasian patients but in no control subjects (p = 0.006 with relative risk of 16.86). HLA-DR2 was significantly associated with Caucasian SLE (R2 = 0.63, p less than 0.0012). Multivariate analysis demonstrated that the HLA-DR2 antigen and C4A null allele contributed independently to the risk of SLE (relative risk 3.0 and 3.2, respectively); when HLA-DR2 and the homozygous C4A null phenotype were present together, the relative risk of SLE was 24.9. Both HLA-B8 and HLA-DR3 were increased in SLE, but these antigens are in linkage disequilibrium with the C4A null allele; the presence of HLA-B8 or DR3 did not contribute further to the risk of SLE. It is concluded that the HLA-DR2 antigen and the C4A null allele are independent and additive risk factors for development of SLE.

Adolescent↗
PubMed1986

Gene conversion in salt-losing congenital adrenal hyperplasia with absent complement C4B protein.

Two of four siblings expressed the salt-losing form of congenital adrenal hyperplasia due to 21-hydroxylase deficiency (CAH) and had identical human lymphocyte antigen (HLA) and complement C4 (fourth component of complement) types (HLA-A3,C4,B35,C4A3,C4BQO,DR1/A2,C-,B18,C4A3, C4BQO,DR6). The father and one unaffected sibling were heterozygous carriers of CAH, as determined by a 30-min iv ACTH stimulation test and HLA typing. In addition, the iv ACTH stimulation test revealed that the mother and the other unaffected sibling also carried an allele for an attenuated form of CAH. Restriction endonuclease digests of genomic DNA obtained from members of this family and from normal unrelated subjects were hybridized with cDNA probes encoding human 21-hydroxylase and C4. With the 21-hydroxylase probe, Southern blots prepared from control DNA samples revealed two major restriction fragments in each of four restriction endonuclease digests; TaqI produced major bands at 3.7 and 3.2 kilobases (kb), KpnI at 4.0 and 2.9 kb, EcoRI at 18 and 13 kb, and BglII at 15 and 12.5 kb. Southern blots prepared from DNA of the two patients lacked the 3.7-kb TaqI and 2.9-kb KpnI fragments, but had increased hybridization intensity (relative to control DNA samples) in the 3.2-kb TaqI and 4.0-kb KpnI fragments. By contrast, blots with EcoRI or BglII had two large hybridization fragments not different from control DNA samples. These data indicate the presence of two different 21-hydroxylase genes. Additional mapping studies revealed that the two genes had the restriction pattern of the inactive 21-hydroxylase gene. When genomic DNA that had been isolated from all members of this family and from normal subjects was hybridized with the human C4 cDNA probe, the restriction fragment hybridization patterns for all four endonuclease digests were similar in the two groups. Hence, our results suggest that the 21-hydroxylase deficiency of our patients is due to conversion of the active 21-hydroxylase gene to the inactive gene. This gene conversion was associated with absence of functional C4B protein, without any detectable alterations in the restriction fragment pattern of the C4 genes.

Adrenal Hyperplasia, Congenital↗