Linkage studies of NIDDM with 23 chromosome 11 markers in a sample of whites of northern European descent

Abstract Mutations of α spectrin (Sp) involving the Sp heterodimer self-association site (the α I domain of Sp) represent the most common group of membrane skeletal defects in hereditary elliptocytosis (HE) and a closely related disorder, hereditary pyropoikilocytosis (HPP). HPP is characterized by extreme anisocytic microcytosis, a severe spectrin dimer self-association defect and spectrin deficiency. The conventional explanation for the different phenotypes is that HPP subjects are compound heterozygotes for an α sp defect that interferes with sp tetramer assembly and a second defect which results in decreased synthesis of functional α sp. In contrast, HE subjects have normal spectrin content and a less severe sp self-association defect. The clinical expression of HE/HPP is influenced by the inheritance of modifying factors such as the α Sp hypomorphic mutation, α LELY. α LELY is a low expression allele of the α Sp gene characterized by a C>G mutation in codon 1857 of exon 40 and a C>T-12 mutation in intron 45 that is responsible for partial skipping of exon 46, which is essential for the functional assembly of α/b sp dimers. Here we describe a family of northern European descent in which members had different erythrocyte morphology ranging from atypical HPP to HE to normal and a novel αSp mutation. Quantitation of RBC membrane proteins of the propositus with atypical non-microcytic HPP revealed 48% spectrin dimers (control 10%) due to a marked increase in the 74kD αI Sp peptide. There was only a slight decrease in the spectrin/band 3 ratio, which correlated with the normocytic morphology. There was also an abnormal α Sp peptide at 41kD suggesting presence of α LELY. Sequencing of his α Sp gene revealed heterozygosity for a novel mutation in exon 2, codon 34: CGG->CCG (Arg>Pro) and heterozygosity for α LELY. These mutations were also present in his brother and daughter who have HE, while another son, who had Arg34Pro, but not α LELY has repeatedly confirmed normal morphology (data in pedigree, figure 1). Ongoing clinical, α Sp peptide, DNA and quantitative Real Time PCR mRNA studies of extended family reveal a complex interaction of codon 34: G>C mutation with α LELY and different levels of transcripts of α Sp alleles. #equal contribution. Figure Figure

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Are pregnant women of non-Northern European descent more anaemic than women of Northern European descent?

Midwifery ◽

10.1016/j.midw.2008.02.001 ◽

2009 ◽

Vol 25 (6) ◽

pp. 766-773 ◽

Cited By ~ 6

Author(s):

S.M.P.J. Jans ◽

D.O.A. Daemers ◽

R. de Vos ◽

A.L.M. Lagro-Jansen

Keyword(s):

Pregnant Women ◽

European Descent ◽

Northern European

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Abstract 3570: Common Mitochondrial Haplogroups Do Not Predict Risk of Ischemic Cardiovascular Disease, Mortality, or Longevity in the General Population

Circulation ◽

10.1161/circ.116.suppl_16.ii_808 ◽

2007 ◽

Vol 116 (suppl_16) ◽

Author(s):

Marianne Benn ◽

Marianne Schwartz ◽

Børge G Nordestgaard ◽

Anne Tybjćrg-Hansen

Keyword(s):

Cardiovascular Disease ◽

General Population ◽

Prospective Study ◽

Mitochondrial Haplogroups ◽

Large Prospective Study ◽

European Descent ◽

Cardiovascular Disease Mortality ◽

Northern European ◽

Hazard Ratios ◽

Disease Mortality

Recently there have been numerous reports suggesting a role for mitochondrial haplogroups, defined by common polymorphisms in the mitochondrial genome, in the pathogenesis of common multifactorial disease such as ischemic cardiovascular disease, and in longevity. These studies have in common that they are all case-control studies with a very limited number of participants, and therefore are prone to selection bias and have very limited power. In the present study, we therefore tested the hypothesis that mitochondrial haplogroups predict risk of ischemic cardiovascular disease, mortality, and longevity in a large prospective study of a general population of Northern European descent. We genotyped 9,254 individuals from the Danish general population, The Copenhagen City Heart Study, for six polymorphisms (mt7028, mt10398, mt11719, mt12308, mt12612, mt15607) defining eight mitochondrial haplogroups, and determined the ability of these haplogroups to predict risk of ischemic cardiovascular disease, mortality, and longevity with, respectively, 25 and 11 years follow-up. Haplogroup frequencies were: H(45.9%), U(15.9%), T(9.9%), J(9.1), K(6.2%), V(4.5%), W/I(3.8%), and Z(3.5%). Multifactorially adjusted hazard ratios for hospitalization due to ischemic heart disease and ischemic cerebrovascular disease as a function of haplogroups were not significantly different from the most common haplogroup H. Furthermore, multifactorially adjusted hazard ratios for death of all causes as well as for major causes of death including ischemic cardiovascular disease as a function of haplogroups were also not significantly different from haplogroup H. Finally, on survival plots, longevity defined as percent surviving as a function of age by haplogroups did not differ when comparing each haplogroup with haplogroup H. In conclusion, in this large prospective study of a general population of Northern European descent mitochondrial haplogroups did not predict risk of ischemic cardiovascular disease, mortality, or longevity. Thus, our results suggest that mitochondrial haplogroups are not major predictors of ischemic cardiovascular disease, overall mortality, mortality from ischemic cardiovascular disease, or longevity in the general population.

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Comparison of linkage disequilibrium patterns between the HapMap CEPH samples and a family-based cohort of Northern European descent

Genomics ◽

10.1016/j.ygeno.2006.04.004 ◽

2006 ◽

Vol 88 (4) ◽

pp. 407-414 ◽

Cited By ~ 16

Author(s):

E.M. Smith ◽

X. Wang ◽

J. Littrell ◽

J. Eckert ◽

R. Cole ◽

...

Keyword(s):

Linkage Disequilibrium ◽

European Descent ◽

Northern European ◽

Family Based

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Obesity-related dyslipidemia associated withFAAH, independent of insulin response, in multigenerational families of Northern European descent

Pharmacogenomics ◽

10.2217/pgs.09.122 ◽

2009 ◽

Vol 10 (12) ◽

pp. 1929-1939 ◽

Cited By ~ 13

Author(s):

Yi Zhang ◽

Gabriele E Sonnenberg ◽

Tesfaye Mersha Baye ◽

Jack Littrell ◽

Jennifer Gunnell ◽

...

Keyword(s):

Insulin Response ◽

European Descent ◽

Multigenerational Families ◽

Northern European

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Disorders of the red cell membrane

Oxford Textbook of Medicine ◽

10.1093/med/9780199204854.003.220510 ◽

2010 ◽

pp. 4461-4468

Author(s):

Patrick G. Gallagher

Keyword(s):

Shear Stress ◽

Cell Membrane ◽

Membrane Lipid ◽

Red Cell ◽

Red Cell Membrane ◽

European Descent ◽

Lipid Interactions ◽

Northern European ◽

Protein 4.2 ◽

Membrane Lipid Bilayer

The integrity of the red-cell membrane depends on molecular interactions between proteins and protein–lipid interactions: vertical interactions stabilize the membrane lipid bilayer; horizontal interactions provide resistance against shear stress. This disorder affects 1 in 25 000 individuals of northern European descent. There is typically a dominant family history, but the condition is genetically heterogeneous: combined spectrin and ankyrin deficiency is the most common defect observed, followed by band 3 deficiency, isolated spectrin deficiency, and protein 4.2 deficiency. These affect vertical membrane interactions with loss of surface area relative to red-cell volume....

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