Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: A clinical and molecular genetic analysis

Marcello Arca, Giovanni Zuliani, Kenneth Wilund, Filomena Campagna, Renato Fellin, Stefano Bertolini, Sebastiano Calandra, Giorgio Ricci, Nicola Glorioso, Mario Maioli, Paolo Pintus, Ciriaco Carru, Fausto Cossu, Jonathan Cohen, Helen H. Hobbs

Research output: Contribution to journalArticle

116 Citations (Scopus)

Abstract

Background. Autosomal recessive hypercholesterolaemia (ARH) is caused by mutations in a putative adaptor protein called ARH. This recessive disorder, characterised by severe hypercholesterolaemia, xanthomatosis, and premature coronary artery disease, is rare except on the island of Sardinia, Italy. Our aim was to ascertain why ARH is more common on Sardinia than elsewhere. Methods. We obtained detailed medical histories, did physical examinations, measured concentrations of lipoproteins, and harvested genomic DNA from 28 Sardinians with ARH from 17 unrelated families. We sequenced the coding regions and consensus splice sites of ARH in probands from these families, and from 40 individuals of non-Sardinian origin who had an autosomal recessive form of hypercholesterolaemia of unknown cause. Findings. Two ARH mutations, a frameshift mutation (c432insA) in exon 4 (ARH1) and a nonsense mutation (c65G→A) in exon 1 (ARH2), were present in all of the 17 unrelated families with ARH. Three of the ARH alleles contained both mutations, as a result of an ancient recombination between ARH1 and ARH2. No regional clustering of the three mutant alleles within Sardinia was apparent. Furthermore, four Italians from the mainland with autosomal recessive hypercholesterolaemia were homozygous for ARH1. Interpretation. The small number, high frequency, and dispersed distribution of ARH mutations on Sardinia are consistent with these mutations being ancient and maintained in the Sardinian population because of geographic isolation.

Original languageEnglish (US)
Pages (from-to)841-847
Number of pages7
JournalLancet
Volume359
Issue number9309
DOIs
StatePublished - Mar 9 2002

Fingerprint

Italy
Molecular Biology
Mutation
Exons
Autosomal Recessive Hypercholesterolemia
Alleles
Xanthomatosis
Frameshift Mutation
Nonsense Codon
Hypercholesterolemia
Islands
Genetic Recombination
Lipoproteins
Physical Examination
Cluster Analysis
Coronary Artery Disease
DNA

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH : A clinical and molecular genetic analysis. / Arca, Marcello; Zuliani, Giovanni; Wilund, Kenneth; Campagna, Filomena; Fellin, Renato; Bertolini, Stefano; Calandra, Sebastiano; Ricci, Giorgio; Glorioso, Nicola; Maioli, Mario; Pintus, Paolo; Carru, Ciriaco; Cossu, Fausto; Cohen, Jonathan; Hobbs, Helen H.

In: Lancet, Vol. 359, No. 9309, 09.03.2002, p. 841-847.

Research output: Contribution to journalArticle

Arca, M, Zuliani, G, Wilund, K, Campagna, F, Fellin, R, Bertolini, S, Calandra, S, Ricci, G, Glorioso, N, Maioli, M, Pintus, P, Carru, C, Cossu, F, Cohen, J & Hobbs, HH 2002, 'Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: A clinical and molecular genetic analysis', Lancet, vol. 359, no. 9309, pp. 841-847. https://doi.org/10.1016/S0140-6736(02)07955-2
Arca, Marcello ; Zuliani, Giovanni ; Wilund, Kenneth ; Campagna, Filomena ; Fellin, Renato ; Bertolini, Stefano ; Calandra, Sebastiano ; Ricci, Giorgio ; Glorioso, Nicola ; Maioli, Mario ; Pintus, Paolo ; Carru, Ciriaco ; Cossu, Fausto ; Cohen, Jonathan ; Hobbs, Helen H. / Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH : A clinical and molecular genetic analysis. In: Lancet. 2002 ; Vol. 359, No. 9309. pp. 841-847.
@article{8e2b1be8743c4925af8ecb1e1fbc68da,
title = "Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH: A clinical and molecular genetic analysis",
abstract = "Background. Autosomal recessive hypercholesterolaemia (ARH) is caused by mutations in a putative adaptor protein called ARH. This recessive disorder, characterised by severe hypercholesterolaemia, xanthomatosis, and premature coronary artery disease, is rare except on the island of Sardinia, Italy. Our aim was to ascertain why ARH is more common on Sardinia than elsewhere. Methods. We obtained detailed medical histories, did physical examinations, measured concentrations of lipoproteins, and harvested genomic DNA from 28 Sardinians with ARH from 17 unrelated families. We sequenced the coding regions and consensus splice sites of ARH in probands from these families, and from 40 individuals of non-Sardinian origin who had an autosomal recessive form of hypercholesterolaemia of unknown cause. Findings. Two ARH mutations, a frameshift mutation (c432insA) in exon 4 (ARH1) and a nonsense mutation (c65G→A) in exon 1 (ARH2), were present in all of the 17 unrelated families with ARH. Three of the ARH alleles contained both mutations, as a result of an ancient recombination between ARH1 and ARH2. No regional clustering of the three mutant alleles within Sardinia was apparent. Furthermore, four Italians from the mainland with autosomal recessive hypercholesterolaemia were homozygous for ARH1. Interpretation. The small number, high frequency, and dispersed distribution of ARH mutations on Sardinia are consistent with these mutations being ancient and maintained in the Sardinian population because of geographic isolation.",
author = "Marcello Arca and Giovanni Zuliani and Kenneth Wilund and Filomena Campagna and Renato Fellin and Stefano Bertolini and Sebastiano Calandra and Giorgio Ricci and Nicola Glorioso and Mario Maioli and Paolo Pintus and Ciriaco Carru and Fausto Cossu and Jonathan Cohen and Hobbs, {Helen H.}",
year = "2002",
month = "3",
day = "9",
doi = "10.1016/S0140-6736(02)07955-2",
language = "English (US)",
volume = "359",
pages = "841--847",
journal = "The Lancet",
issn = "0140-6736",
publisher = "Elsevier Limited",
number = "9309",

}

TY - JOUR

T1 - Autosomal recessive hypercholesterolaemia in Sardinia, Italy, and mutations in ARH

T2 - A clinical and molecular genetic analysis

AU - Arca, Marcello

AU - Zuliani, Giovanni

AU - Wilund, Kenneth

AU - Campagna, Filomena

AU - Fellin, Renato

AU - Bertolini, Stefano

AU - Calandra, Sebastiano

AU - Ricci, Giorgio

AU - Glorioso, Nicola

AU - Maioli, Mario

AU - Pintus, Paolo

AU - Carru, Ciriaco

AU - Cossu, Fausto

AU - Cohen, Jonathan

AU - Hobbs, Helen H.

PY - 2002/3/9

Y1 - 2002/3/9

N2 - Background. Autosomal recessive hypercholesterolaemia (ARH) is caused by mutations in a putative adaptor protein called ARH. This recessive disorder, characterised by severe hypercholesterolaemia, xanthomatosis, and premature coronary artery disease, is rare except on the island of Sardinia, Italy. Our aim was to ascertain why ARH is more common on Sardinia than elsewhere. Methods. We obtained detailed medical histories, did physical examinations, measured concentrations of lipoproteins, and harvested genomic DNA from 28 Sardinians with ARH from 17 unrelated families. We sequenced the coding regions and consensus splice sites of ARH in probands from these families, and from 40 individuals of non-Sardinian origin who had an autosomal recessive form of hypercholesterolaemia of unknown cause. Findings. Two ARH mutations, a frameshift mutation (c432insA) in exon 4 (ARH1) and a nonsense mutation (c65G→A) in exon 1 (ARH2), were present in all of the 17 unrelated families with ARH. Three of the ARH alleles contained both mutations, as a result of an ancient recombination between ARH1 and ARH2. No regional clustering of the three mutant alleles within Sardinia was apparent. Furthermore, four Italians from the mainland with autosomal recessive hypercholesterolaemia were homozygous for ARH1. Interpretation. The small number, high frequency, and dispersed distribution of ARH mutations on Sardinia are consistent with these mutations being ancient and maintained in the Sardinian population because of geographic isolation.

AB - Background. Autosomal recessive hypercholesterolaemia (ARH) is caused by mutations in a putative adaptor protein called ARH. This recessive disorder, characterised by severe hypercholesterolaemia, xanthomatosis, and premature coronary artery disease, is rare except on the island of Sardinia, Italy. Our aim was to ascertain why ARH is more common on Sardinia than elsewhere. Methods. We obtained detailed medical histories, did physical examinations, measured concentrations of lipoproteins, and harvested genomic DNA from 28 Sardinians with ARH from 17 unrelated families. We sequenced the coding regions and consensus splice sites of ARH in probands from these families, and from 40 individuals of non-Sardinian origin who had an autosomal recessive form of hypercholesterolaemia of unknown cause. Findings. Two ARH mutations, a frameshift mutation (c432insA) in exon 4 (ARH1) and a nonsense mutation (c65G→A) in exon 1 (ARH2), were present in all of the 17 unrelated families with ARH. Three of the ARH alleles contained both mutations, as a result of an ancient recombination between ARH1 and ARH2. No regional clustering of the three mutant alleles within Sardinia was apparent. Furthermore, four Italians from the mainland with autosomal recessive hypercholesterolaemia were homozygous for ARH1. Interpretation. The small number, high frequency, and dispersed distribution of ARH mutations on Sardinia are consistent with these mutations being ancient and maintained in the Sardinian population because of geographic isolation.

UR - http://www.scopus.com/inward/record.url?scp=0037045847&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=0037045847&partnerID=8YFLogxK

U2 - 10.1016/S0140-6736(02)07955-2

DO - 10.1016/S0140-6736(02)07955-2

M3 - Article

C2 - 11897284

AN - SCOPUS:0037045847

VL - 359

SP - 841

EP - 847

JO - The Lancet

JF - The Lancet

SN - 0140-6736

IS - 9309

ER -