BACKGROUND: Homozygous familial hypercholesterolemia is a rare clinical phenotype with a variable expression, which is characterized by extremely elevated plasma low-density lipoprotein (LDL), tendon and skin xanthomas, and a progressive atherosclerosis. In 95% of patients, homozygous familial hypercholesterolemia is due to mutations in low-density lipoprotein receptor (LDLR) gene, which abolish (receptor-negative) or greatly reduce (receptor-defective) LDLR function. OBJECTIVE: The objective of the study was the molecular and phenotypic characterization of 4 siblings with severe hypercholesterolemia. METHODS: The major LDL-related genes (LDLR, APOB, PCSK9, ANGPTL3, APOE, and APOC3) were sequenced. LDLR messenger RNA, isolated from leukocytes, was reverse transcribed and sequenced. RESULTS: The index cases were 24-year-old identical twin sisters with long-standing tendon xanthomas and high low-density lipoprotein cholesterol (LDL-C w10 mmol/L) but no coronary heart disease. They were carriers of 2 LDLR mutations: (1) a previously reported mutation [p.(G335S)] inherited from the mother who had LDL-C level within normal range; (2) a novel 24 bp deletion in exon 8/intron 8 junction inherited from the hypercholesterolemic (LDL-C 6.1 mmol/L) father. The deletion allele encodes an messenger RNA with a partial deletion of exon 8, whose translation product has an in-frame deletion of 17 amino acids [p.(Glu380_Gly396- del)]. Family screening revealed that the 2 siblings of the twin sisters were also compound heterozygotes but had much lower LDL-C levels (8.2 and 7.1 mmol/L). The sequence of potential modifying genes showed that the 2 siblings and the mother of the twin sisters were heterozygous for a rare missense variant of apoB [p.(S2429T)], which might have an LDL-lowering effect.

Phenotypic variability in 4 homozygous familial hypercholesterolemia siblings compound heterozygous for LDLR mutations / Rabacchi, Claudio; Bigazzi, F; Puntoni, M; Sbrana, F; Sampietro, T; Tarugi, Patrizia Maria; Bertolini, S; Calandra, S.. - In: JOURNAL OF CLINICAL LIPIDOLOGY. - ISSN 1933-2874. - STAMPA. - 10:(2016), pp. 944-952. [10.1016/j.jacl.2016.04.005]

Phenotypic variability in 4 homozygous familial hypercholesterolemia siblings compound heterozygous for LDLR mutations

RABACCHI, CLAUDIO;TARUGI, Patrizia Maria;
2016

Abstract

BACKGROUND: Homozygous familial hypercholesterolemia is a rare clinical phenotype with a variable expression, which is characterized by extremely elevated plasma low-density lipoprotein (LDL), tendon and skin xanthomas, and a progressive atherosclerosis. In 95% of patients, homozygous familial hypercholesterolemia is due to mutations in low-density lipoprotein receptor (LDLR) gene, which abolish (receptor-negative) or greatly reduce (receptor-defective) LDLR function. OBJECTIVE: The objective of the study was the molecular and phenotypic characterization of 4 siblings with severe hypercholesterolemia. METHODS: The major LDL-related genes (LDLR, APOB, PCSK9, ANGPTL3, APOE, and APOC3) were sequenced. LDLR messenger RNA, isolated from leukocytes, was reverse transcribed and sequenced. RESULTS: The index cases were 24-year-old identical twin sisters with long-standing tendon xanthomas and high low-density lipoprotein cholesterol (LDL-C w10 mmol/L) but no coronary heart disease. They were carriers of 2 LDLR mutations: (1) a previously reported mutation [p.(G335S)] inherited from the mother who had LDL-C level within normal range; (2) a novel 24 bp deletion in exon 8/intron 8 junction inherited from the hypercholesterolemic (LDL-C 6.1 mmol/L) father. The deletion allele encodes an messenger RNA with a partial deletion of exon 8, whose translation product has an in-frame deletion of 17 amino acids [p.(Glu380_Gly396- del)]. Family screening revealed that the 2 siblings of the twin sisters were also compound heterozygotes but had much lower LDL-C levels (8.2 and 7.1 mmol/L). The sequence of potential modifying genes showed that the 2 siblings and the mother of the twin sisters were heterozygous for a rare missense variant of apoB [p.(S2429T)], which might have an LDL-lowering effect.
2016
21-apr-2016
10
944
952
Phenotypic variability in 4 homozygous familial hypercholesterolemia siblings compound heterozygous for LDLR mutations / Rabacchi, Claudio; Bigazzi, F; Puntoni, M; Sbrana, F; Sampietro, T; Tarugi, Patrizia Maria; Bertolini, S; Calandra, S.. - In: JOURNAL OF CLINICAL LIPIDOLOGY. - ISSN 1933-2874. - STAMPA. - 10:(2016), pp. 944-952. [10.1016/j.jacl.2016.04.005]
Rabacchi, Claudio; Bigazzi, F; Puntoni, M; Sbrana, F; Sampietro, T; Tarugi, Patrizia Maria; Bertolini, S; Calandra, S.
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11380/1126225
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