Variable expressivity and co-occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy
Background:
The familial inherited genetic disorder of lipoprotein metabolism affects more than 10 million individuals around the world. Lebanon is one of the several endemic areas for familial hypercholesterolemia (FH) with a founder mutation in the low-density lipoprotein cholesterol receptor (LDLR) gene, responsible for most of the cases. We have previously shown that 16% of all familial cases with hypercholesterolemia do not show genotype segregation of LDLR with the underlying phenotype.
Methods:
We used Sanger sequencing to genotype 25 Lebanese families with severe FH for the gene encoding the LDLR-associated protein (LDLRAP1), responsible for the recessive form of the disease starting with the four families that did not show any genotype-phenotype correlation in our previous screening.
Results:
We showed that the previously reported p.Q136* variant is linked to the hypercholesterolemia phenotype in the four families. In addition, we showed a variable phenotype between families and between members of the same family. One family exhibits mutations in both LDLRand LDLRAP1 with family members showing differential phenotypes unexplained by the underlying genotypes of the two genes.
Conclusion:
The p.Q136* variant in LDLRAP1 is yet another founder mutation in Lebanon and coupled with the LDLR p.C681* variant explains all the genetic causes of FH in Lebanon.
Keywords:
Familial Hypercholesterolemia, LDLRAP1, LDLR, founder mutation
Autoři:
Akl C. Fahed 1,2; Ruby Khalaf 1; Rony Salloum 1; Rabih R. Andary 1; Raya Safa 1; Inaam El-Rassy 1; Elie Moubarak 3; Sami T. Azar 4; Fadi F. Bitar 5; Georges Nemer 1,*
Působiště autorů:
Department of Biochemistry and Molecular Genetics, American University of Beirut, Beirut, Lebanon
1; Department of Genetics, Harvard Medical School and Department of Internal Medicine, Massachusetts General Hospital, Boston, Massachusetts
2; National LDL Apheresis Center, Dahr El-Bashek Governmental University Hospital, Roumieh, Lebanon
3; Department of Internal Medicine, American University of Beirut, Beirut, Lebanon
4; Department of Pediatrics and Adolescent Medicine, American University of Beirut, Beirut, Lebanon
5
Vyšlo v časopise:
Molecular Genetics & Genomic Medicine 2016; 4(3)
Kategorie:
Original article
prolekare.web.journal.doi_sk:
https://doi.org/10.1002/mgg3.203
© 2016 The Authors. Molecular Genetics & Genomic Medicine published by Wiley Periodicals, Inc.
This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
Souhrn
Background:
The familial inherited genetic disorder of lipoprotein metabolism affects more than 10 million individuals around the world. Lebanon is one of the several endemic areas for familial hypercholesterolemia (FH) with a founder mutation in the low-density lipoprotein cholesterol receptor (LDLR) gene, responsible for most of the cases. We have previously shown that 16% of all familial cases with hypercholesterolemia do not show genotype segregation of LDLR with the underlying phenotype.
Methods:
We used Sanger sequencing to genotype 25 Lebanese families with severe FH for the gene encoding the LDLR-associated protein (LDLRAP1), responsible for the recessive form of the disease starting with the four families that did not show any genotype-phenotype correlation in our previous screening.
Results:
We showed that the previously reported p.Q136* variant is linked to the hypercholesterolemia phenotype in the four families. In addition, we showed a variable phenotype between families and between members of the same family. One family exhibits mutations in both LDLRand LDLRAP1 with family members showing differential phenotypes unexplained by the underlying genotypes of the two genes.
Conclusion:
The p.Q136* variant in LDLRAP1 is yet another founder mutation in Lebanon and coupled with the LDLR p.C681* variant explains all the genetic causes of FH in Lebanon.
Keywords:
Familial Hypercholesterolemia, LDLRAP1, LDLR, founder mutation
Zdroje
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Štítky
GenetikaČlánok vyšiel v časopise
Molecular Genetics & Genomic Medicine
2016 Číslo 3
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