Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population

Annette Haagerup, Jens Michael Hertz, M F Christensen, Helle Glud Binderup, T A Kruse

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

Resumé

The molecular genetics of the autosomal recessive disorder pycnodysostosis was studied in five independent families from an outbred Caucasian population. We found two new mutations and one recently described mutation in the cathepsin K gene by sequencing DNA from eight patients with pycnodysostosis: a one base transition in exon8, c926T > C, causing a single amino acid substitution leucine-->proline, L309P; A 3' splice site mutation in intron 2, c121-1G > A, causing deletion of all exon 3, 41V-81Mdel; and the exon 3 missense mutation c236G > A leading to residue G79E. In three of the families patients were homozygous for 926T > C. In the remaining two families patients were heterozygous for 926T > C and 121-1G > A in one case, and for 926T > C and 236G > A in the other case. Assays using genomic DNA were developed for all three mutations. We tested 150 healthy control persons and observed the mutation frequencies: 0 to 300 for 121-1G > A and 236G > A and 1 to 150 for 926T > C. One patient from each family was haplotyped with eight microsatellite markers surrounding the cathepsin K gene on chromosome 1q21. A very rare, P = 1.8 x 10(-6) to P = 0.0004, and highly preserved area around the presumed disease locus was common to all the patients. This haplotype was found on seven chromosomes identical by state, IBS, out of the possible eight carrying the 926T > C mutation. Founder effect, locus homogeneity, and allele heterogeneity regarding pycnodysostosis within this population are discussed. Finally, the first pregnancy and delivery described in a patient with pycnodysostosis is reported.
OriginalsprogEngelsk
TidsskriftEuropean Journal of Human Genetics
Vol/bind8
Udgave nummer6
Sider (fra-til)431-6
Antal sider6
ISSN1018-4813
DOI
StatusUdgivet - 2000

Fingeraftryk

Cathepsin K
Haplotypes
Mutation
Population
Founder Effect
RNA Splice Sites
Mutation Rate
Missense Mutation
Amino Acid Substitution
DNA Sequence Analysis
Leucine
Introns
Alleles
DNA

Citer dette

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title = "Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population",
abstract = "The molecular genetics of the autosomal recessive disorder pycnodysostosis was studied in five independent families from an outbred Caucasian population. We found two new mutations and one recently described mutation in the cathepsin K gene by sequencing DNA from eight patients with pycnodysostosis: a one base transition in exon8, c926T > C, causing a single amino acid substitution leucine-->proline, L309P; A 3' splice site mutation in intron 2, c121-1G > A, causing deletion of all exon 3, 41V-81Mdel; and the exon 3 missense mutation c236G > A leading to residue G79E. In three of the families patients were homozygous for 926T > C. In the remaining two families patients were heterozygous for 926T > C and 121-1G > A in one case, and for 926T > C and 236G > A in the other case. Assays using genomic DNA were developed for all three mutations. We tested 150 healthy control persons and observed the mutation frequencies: 0 to 300 for 121-1G > A and 236G > A and 1 to 150 for 926T > C. One patient from each family was haplotyped with eight microsatellite markers surrounding the cathepsin K gene on chromosome 1q21. A very rare, P = 1.8 x 10(-6) to P = 0.0004, and highly preserved area around the presumed disease locus was common to all the patients. This haplotype was found on seven chromosomes identical by state, IBS, out of the possible eight carrying the 926T > C mutation. Founder effect, locus homogeneity, and allele heterogeneity regarding pycnodysostosis within this population are discussed. Finally, the first pregnancy and delivery described in a patient with pycnodysostosis is reported.",
keywords = "Adolescent, Adult, Amino Acid Substitution, Cathepsin K, Cathepsins, Child, Child, Preschool, Chromosomes, Human, Pair 1, DNA Mutational Analysis, Dysostoses, European Continental Ancestry Group, Exons, Female, Haplotypes, Humans, Male, Microsatellite Repeats, Middle Aged, Mutation, Missense, Pedigree, Polymorphism, Restriction Fragment Length, Pregnancy, RNA Splicing, Sequence Deletion",
author = "Annette Haagerup and Hertz, {Jens Michael} and Christensen, {M F} and Binderup, {Helle Glud} and Kruse, {T A}",
year = "2000",
doi = "10.1038/sj.ejhg.5200481",
language = "English",
volume = "8",
pages = "431--6",
journal = "European Journal of Human Genetics",
issn = "1018-4813",
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Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population. / Haagerup, Annette; Hertz, Jens Michael; Christensen, M F; Binderup, Helle Glud; Kruse, T A.

I: European Journal of Human Genetics, Bind 8, Nr. 6, 2000, s. 431-6.

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

TY - JOUR

T1 - Cathepsin K gene mutations and 1q21 haplotypes in at patients with pycnodysostosis in an outbred population

AU - Haagerup, Annette

AU - Hertz, Jens Michael

AU - Christensen, M F

AU - Binderup, Helle Glud

AU - Kruse, T A

PY - 2000

Y1 - 2000

N2 - The molecular genetics of the autosomal recessive disorder pycnodysostosis was studied in five independent families from an outbred Caucasian population. We found two new mutations and one recently described mutation in the cathepsin K gene by sequencing DNA from eight patients with pycnodysostosis: a one base transition in exon8, c926T > C, causing a single amino acid substitution leucine-->proline, L309P; A 3' splice site mutation in intron 2, c121-1G > A, causing deletion of all exon 3, 41V-81Mdel; and the exon 3 missense mutation c236G > A leading to residue G79E. In three of the families patients were homozygous for 926T > C. In the remaining two families patients were heterozygous for 926T > C and 121-1G > A in one case, and for 926T > C and 236G > A in the other case. Assays using genomic DNA were developed for all three mutations. We tested 150 healthy control persons and observed the mutation frequencies: 0 to 300 for 121-1G > A and 236G > A and 1 to 150 for 926T > C. One patient from each family was haplotyped with eight microsatellite markers surrounding the cathepsin K gene on chromosome 1q21. A very rare, P = 1.8 x 10(-6) to P = 0.0004, and highly preserved area around the presumed disease locus was common to all the patients. This haplotype was found on seven chromosomes identical by state, IBS, out of the possible eight carrying the 926T > C mutation. Founder effect, locus homogeneity, and allele heterogeneity regarding pycnodysostosis within this population are discussed. Finally, the first pregnancy and delivery described in a patient with pycnodysostosis is reported.

AB - The molecular genetics of the autosomal recessive disorder pycnodysostosis was studied in five independent families from an outbred Caucasian population. We found two new mutations and one recently described mutation in the cathepsin K gene by sequencing DNA from eight patients with pycnodysostosis: a one base transition in exon8, c926T > C, causing a single amino acid substitution leucine-->proline, L309P; A 3' splice site mutation in intron 2, c121-1G > A, causing deletion of all exon 3, 41V-81Mdel; and the exon 3 missense mutation c236G > A leading to residue G79E. In three of the families patients were homozygous for 926T > C. In the remaining two families patients were heterozygous for 926T > C and 121-1G > A in one case, and for 926T > C and 236G > A in the other case. Assays using genomic DNA were developed for all three mutations. We tested 150 healthy control persons and observed the mutation frequencies: 0 to 300 for 121-1G > A and 236G > A and 1 to 150 for 926T > C. One patient from each family was haplotyped with eight microsatellite markers surrounding the cathepsin K gene on chromosome 1q21. A very rare, P = 1.8 x 10(-6) to P = 0.0004, and highly preserved area around the presumed disease locus was common to all the patients. This haplotype was found on seven chromosomes identical by state, IBS, out of the possible eight carrying the 926T > C mutation. Founder effect, locus homogeneity, and allele heterogeneity regarding pycnodysostosis within this population are discussed. Finally, the first pregnancy and delivery described in a patient with pycnodysostosis is reported.

KW - Adolescent

KW - Adult

KW - Amino Acid Substitution

KW - Cathepsin K

KW - Cathepsins

KW - Child

KW - Child, Preschool

KW - Chromosomes, Human, Pair 1

KW - DNA Mutational Analysis

KW - Dysostoses

KW - European Continental Ancestry Group

KW - Exons

KW - Female

KW - Haplotypes

KW - Humans

KW - Male

KW - Microsatellite Repeats

KW - Middle Aged

KW - Mutation, Missense

KW - Pedigree

KW - Polymorphism, Restriction Fragment Length

KW - Pregnancy

KW - RNA Splicing

KW - Sequence Deletion

U2 - 10.1038/sj.ejhg.5200481

DO - 10.1038/sj.ejhg.5200481

M3 - Journal article

C2 - 10878663

VL - 8

SP - 431

EP - 436

JO - European Journal of Human Genetics

JF - European Journal of Human Genetics

SN - 1018-4813

IS - 6

ER -