PMID- 10924730
OWN - NLM
STAT- MEDLINE
DCOM- 20001121
LR  - 20190718
IS  - 0021-9150 (Print)
IS  - 0021-9150 (Linking)
VI  - 151
IP  - 2
DP  - 2000 Aug
TI  - FH-Freiburg: a novel missense mutation (C317Y) in growth factor repeat A of the 
      low density lipoprotein receptor gene in a German patient with homozygous 
      familial hypercholesterolemia.
PG  - 525-34
AB  - We describe the characterization of a novel mutation in the low density 
      lipoprotein receptor (LDL-R) gene in a patient with true homozygous familial 
      hypercholesterolemia (FH). The combined use of denaturing gradient gel 
      electrophoresis (DGGE) and sequencing of genomic DNA revealed a guanine to 
      adenine base substitution at nucleotide position 1013 of the LDL-R cDNA. This 
      point mutation results in a change from cysteine to tyrosine at amino acid 
      residue 317 of repeat A of the epidermal growth factor (EGF) precursor homology 
      domain. Binding, uptake and degradation of iodinated LDL in skin fibroblasts from 
      the homozygous patient were less than 10% of normal. In contrast, binding, uptake 
      and degradation of iodinated VLDL was reduced by only 60, 30, and 38%, 
      respectively. Incubation of the patient's fibroblasts in the presence of 
      cholesterol diminished the residual binding of VLDL by 50%, suggesting that the 
      loss of the highly conserved cysteine at position 317 results in a LDL-R that 
      fails to bind LDL, but retains some ability to bind VLDL by interacting with the 
      apolipoprotein E. Both parents were heterozygous for the C317Y mutation. 
      Interestingly, however, the father presented with markedly elevated levels of 
      triglycerides and VLDL cholesterol, whereas his LDL cholesterol was unexpectedly 
      low. The mother of the index patient had only slightly elevated LDL cholesterol. 
      These observations testify to the biological complexity of genotype-environment 
      interactions in individuals carrying mutations at the LDL-R locus and indicate 
      that genetic analysis importantly complements the clinical and biochemical 
      diagnosis of patients with hyperlipidemia.
FAU - Nauck, M S
AU  - Nauck MS
AD  - Department of Clinical Chemistry, University Hospital, Freiburg, Germany. 
      msnauck@med1.ukl.uni-freiburg.de
FAU - Scharnagl, H
AU  - Scharnagl H
FAU - Nissen, H
AU  - Nissen H
FAU - Schurmann, C
AU  - Schurmann C
FAU - Matern, D
AU  - Matern D
FAU - Nauck, M A
AU  - Nauck MA
FAU - Wieland, H
AU  - Wieland H
FAU - Marz, W
AU  - Marz W
LA  - eng
PT  - Case Reports
PT  - Journal Article
PL  - Ireland
TA  - Atherosclerosis
JT  - Atherosclerosis
JID - 0242543
RN  - 0 (Lipoproteins)
RN  - 0 (Receptors, LDL)
RN  - 62229-50-9 (Epidermal Growth Factor)
SB  - IM
EIN - Atherosclerosis. 2003 Mar;167(1):173.. Mattern D [corrected to Matern D]
MH  - Adolescent
MH  - Adult
MH  - Alleles
MH  - Base Sequence/genetics
MH  - Cells, Cultured
MH  - Child
MH  - Epidermal Growth Factor/genetics
MH  - Female
MH  - Fibroblasts/metabolism
MH  - Genotype
MH  - Haplotypes
MH  - *Homozygote
MH  - Humans
MH  - Hyperlipoproteinemia Type II/*genetics
MH  - Lipoproteins/metabolism
MH  - Male
MH  - Middle Aged
MH  - *Mutation, Missense/genetics
MH  - Pedigree
MH  - Receptors, LDL/*genetics
MH  - Repetitive Sequences, Nucleic Acid
MH  - Skin/metabolism/pathology
EDAT- 2000/08/05 11:00
MHDA- 2001/02/28 10:01
CRDT- 2000/08/05 11:00
PHST- 2000/08/05 11:00 [pubmed]
PHST- 2001/02/28 10:01 [medline]
PHST- 2000/08/05 11:00 [entrez]
AID - S0021-9150(99)00415-3 [pii]
AID - 10.1016/s0021-9150(99)00415-3 [doi]
PST - ppublish
SO  - Atherosclerosis. 2000 Aug;151(2):525-34. doi: 10.1016/s0021-9150(99)00415-3.