Identification of a point mutation in growth factor repeat C of the low density lipoprotein-receptor gene in a patient with homozygous familial hypercholesterolemia

Journal Article · Thu Jun 01 04:00:00 EDT 1989 · Proceedings of the National Academy of Sciences of the United States of America; (USA)

DOI:https://doi.org/10.1073/pnas.86.11.4166· OSTI ID:5264401

Soutar, A K; Knight, B L; Patel, D D ^[1]

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1. Hammersmith Hospital, London (England)

The coding region of the low density lipoprotein (LDL)-receptor gene from a patient (MM) with homozygous familial hypercholesterolemia (FH) has been sequenced from six overlapping 500-base-pair amplified fragments of the cDNA from cultured skin fibroblasts. Two separate single nucleotide base changes from the normal sequence were detected. The first involved substitution of guanine for adenine in the third position of the codon for amino acid residue Cys-27 and did not affect the protein sequence. The second mutation was substitution of thymine for cytosine in the DNA for the codon for amino acid residue 664, changing the codon from CCG (proline) to CTG (leucine) and introducing a new site for the restriction enzyme PstI. MM is a true homozygote with two identical genes, and the mutation cosegregated with clinically diagnosed FH in his family in which first cousin marriages occurred frequently. LDL receptors in MM's skin fibroblasts bind less LDL than normal and with reduced affinity. Thus this naturally occurring single point mutation affects both intracellular transport of the protein and ligand binding and occurs in growth factor-like repeat C, a region that has not previously been found to influence LDL binding.

• OSTI ID: 5264401
• Journal Information: Proceedings of the National Academy of Sciences of the United States of America; (USA), Journal Name: Proceedings of the National Academy of Sciences of the United States of America; (USA) Vol. 86:11; ISSN PNASA; ISSN 0027-8424
• Country of Publication: United States
• Language: English

Related Subjects

550201* -- Biochemistry-- Tracer Techniques
59 BASIC BIOLOGICAL SCIENCES
ANIMAL CELLS
CARDIOVASCULAR DISEASES
CHOLESTEROL
CONNECTIVE TISSUE CELLS
DISEASES
DNA SEQUENCING
FIBROBLASTS
GENE MUTATIONS
GENES
GROWTH FACTORS
HEREDITARY DISEASES
HYDROXY COMPOUNDS
LIPIDS
LIPOPROTEINS
MEMBRANE PROTEINS
MEMBRANES
MITOGENS
MOLECULAR STRUCTURE
MUTATIONS
ORGANIC COMPOUNDS
PATHOGENESIS
PATIENTS
PROTEINS
RECEPTORS
SOMATIC CELLS
STEROIDS
STEROLS
STRUCTURAL CHEMICAL ANALYSIS