Extended MHC Haplotypes in 21-Hydroxylase-Deficiency Congenital Adrenal Hyperplasia: Shared Genotypes in Unrelated Patients

Fleischnick, E.; Raum, Donald; Alosco, S.; Gerald, Park S.; Yunis, Edmond J.; Awdeh, Z; Granados, Jesús Benítez; Crigler, John F.; Giles, Carolyn M.; Alper, Chester A.

doi:10.1016/s0140-6736(83)92757-5

Cited by 67 publications

(25 citation statements)

References 24 publications

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“…GLO per se is, of course, not a marker for type I diabetes mellitus, as shown in this and previous studies (1 1, 31). Kirk et (35), is rare. The disease gene has a frequency of <1%, although it is fully penetrant, and the extended haplotype marking it is rare (<0.003) in the normal population.…”

Section: Resultsmentioning

confidence: 99%

Extended major histocompatibility complex haplotypes in type I diabetes mellitus.

Raum¹,

Awdeh²,

Yunis³

et al. 1984

J. Clin. Invest.

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158

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Section: Resultsmentioning

confidence: 99%

Extended major histocompatibility complex haplotypes in type I diabetes mellitus.

Raum¹,

Awdeh²,

Yunis³

et al. 1984

J. Clin. Invest.

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158

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“…With the exception ofHLA-Bw47, DR7, these haplotypes differ in HLA type as well as in complotype. The extended haplotype Bw47, DR7, FC91,0 has a fiequency of >20% among CAH patients (19). The functional 21-OHB gene (6) and the C4B gene are deleted in this haplotype.…”

Section: Discussionmentioning

confidence: 98%

“…The analysis of the structural basis of C4 null alleles by recombinant DNA techniques may help to describe mechanisms leading to duplications and deletions as well as to understand the effect ofthese events in regard to possible autoimmune disease associations (15,17,43). In the case of CAH, a close genetic linkage of this disease to a limited number of MHC-haplotypes has been established (18,19). This linkage is due to the location ofthe gene for steroid 2 1-hydroxylase within the C4 region.…”

Section: Discussionmentioning

confidence: 99%

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Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants.

Schneider¹,

Carroll²,

Alper³

et al. 1986

J. Clin. Invest.

236

113

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Several autoimmune disorders as well as congenital adrenal hyperplasia (CAH) are either associated or closely linked with genetic variants of the fourth component of complement (C4A and C4B) and the enzyme steroid 21-hydroxylase (21-OH). These proteins are encoded by genes that are located downstream from the genes for complement proteins, C2 and factor B (BF) between HLA-B and -DR in the major histocompatibility complex (MHC). Previous studies of variants and null alleles were based on electrophoretic mobility ofC4 protein and linkage with disease phenotypes. These data did not permit analysis of the basis for the observed null alleles and duplicated variants. We studied this region ofthe MHC in 126 haplotypes for a structural analysis of the four adjacent loci, C4A, 21-OHA, C4B, and 21-OHB. About half of the C4 genes typed as C4 null are deleted and several unrecognized homoduplicated C4 alleles were detected.Hence the frequencies of different C4 structural variants must be recalculated based on a direct analysis of the genes. Analysis of the C4/21-OH genes of patients with the classical (salt-wasting) form of CAH showed that some involve a deletion of the C4B and 21-OHB genes; whereas for two only the 21-OHB gene is deleted, i.e., the C4B gene is present. Together, these data provide a better understanding of the mechanisms generating and importance of deleted C4 and 21-OH null alleles in human disease.

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“…These did not appear to differ materially from our general Caucasian population in Boston. the chromosomes of patients with 2 1-hydroxylase deficiency congenital adrenal hyperplasia (24). The gene for that disorder is known to be in the MHC (25)(26)(27).…”

Section: Methodsmentioning

confidence: 99%

Extended major histocompatibility complex haplotypes in patients with gluten-sensitive enteropathy.

Alper¹,

Fleischnick²,

Awdeh³

et al. 1987

J. Clin. Invest.

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We have studied major histocompatibility complex markers in randomly ascertained Caucasian patients with gluten-sensitive enteropathy and their families. The frequencies of extended haplotypes, defined as haplotypes of specific HLA-B, DR, BF, C2, C4A, and C4B allelic combinations, occurring more frequently than expected, were compared on patient chromosomes, on normal chromosomes from the study families, and on chromosomes from normal families. Over half of patient chromosomes consisted almost entirely of two extended haplotypes [HLA-B8, DR3, SCO1j and [HLA-B44, DR7, FC311 which, with nonextended HLA-DR7, accounted for the previously observed HLA markers of this disease: HLA-B8, DR3, and DR7. There was no increase in HLA-DR3 on nonextended haplotypes or in other extended haplotypes with HLA-DR3 or DR7. The distribution of homozygotes and heterozygotes for HLA-DR3 and DR7 was consistent with recessive inheritance of the major histocompatibility complex-linked susceptibility gene for gluten-sensitive enteropathy. On the other hand, by odds ratio analysis and from the sum of DR3 and DR7 homozygotes compared with DR3/ DR7 heterozygotes, there was an increase in heterozygotes and a decrease in homozygotes suggesting the presence of modifying phenomena.

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Extended MHC Haplotypes in 21-Hydroxylase-Deficiency Congenital Adrenal Hyperplasia: Shared Genotypes in Unrelated Patients

Cited by 67 publications

References 24 publications

Extended major histocompatibility complex haplotypes in type I diabetes mellitus.

Extended major histocompatibility complex haplotypes in type I diabetes mellitus.

Polymorphism of the human complement C4 and steroid 21-hydroxylase genes. Restriction fragment length polymorphisms revealing structural deletions, homoduplications, and size variants.

Extended major histocompatibility complex haplotypes in patients with gluten-sensitive enteropathy.

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