Advertisement

Novel combined variants of LDLR and LDLRAP1 genes causing severe familial hypercholesterolemia

  • Author Footnotes
    1 Equal contribution and shared first authorship.
    Fahad Alnouri
    Correspondence
    Corresponding author. Cardiovascular Prevention Unit, Department of Adult Cardiology, Prince Sultan Cardiac Centre Riyadh, P.O box 7897, In-hospital box (X 1003), Riyadh, 11159, Saudi Arabia.
    Footnotes
    1 Equal contribution and shared first authorship.
    Affiliations
    Cardiovascular Prevention Unit, Department of Adult Cardiology, Prince Sultan Cardiac Centre, Riyadh, Saudi Arabia
    Search for articles by this author
  • Author Footnotes
    1 Equal contribution and shared first authorship.
    Mohammad Athar
    Correspondence
    Corresponding author. Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Al-Abedia Campus, P.O Box 715, Makkah, 21955, Saudi Arabia.
    Footnotes
    1 Equal contribution and shared first authorship.
    Affiliations
    Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia

    Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia
    Search for articles by this author
  • Faisal A. Al-Allaf
    Affiliations
    Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia

    Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia

    Molecular Diagnostics Unit, Department of Laboratory and Blood Bank, King Abdullah Medical City, Makkah, Saudi Arabia
    Search for articles by this author
  • Zainularifeen Abduljaleel
    Affiliations
    Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia

    Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia
    Search for articles by this author
  • Mohiuddin M. Taher
    Affiliations
    Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia

    Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia
    Search for articles by this author
  • Abdellatif Bouazzaoui
    Affiliations
    Department of Medical Genetics, Faculty of Medicine, Umm Al-Qura University, Makkah, Saudi Arabia

    Science and Technology Unit, Umm Al-Qura University, Makkah, Saudi Arabia
    Search for articles by this author
  • Dalal Al Ammari
    Affiliations
    Department of Dermatology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia
    Search for articles by this author
  • Hussam Karrar
    Affiliations
    Cardiovascular Prevention Unit, Department of Adult Cardiology, Prince Sultan Cardiac Centre, Riyadh, Saudi Arabia
    Search for articles by this author
  • Monirah Albabtain
    Affiliations
    Cardiovascular Prevention Unit, Department of Adult Cardiology, Prince Sultan Cardiac Centre, Riyadh, Saudi Arabia
    Search for articles by this author
  • Author Footnotes
    1 Equal contribution and shared first authorship.

      Highlights

      • Familial hypercholesterolemia is very much under-reported in Saudi Arabia.
      • Its prevalence and molecular characteristics are not accurately described.
      • It is estimated that 55% of marriages in the country are within the same extended family.
      • Therefore, it is expected to have a higher occurrence than neighbouring countries due to high consanguinity marriages.
      • Existence of recessive and dominant forms of FH within the same family represents an important challenge for management.

      Abstract

      Background and aims

      Familial hypercholesterolemia (FH) is a predominantly autosomal dominant hereditary disorder with significant potential for expansion of coronary artery disease.

      Methods

      To identify candidate variant/s in FH phenotype implicated genes, next-generation sequencing was performed using a targeted customized gene panel.

      Results

      We recognized a 45-year-old Saudi female FH patient with double variants in the LDLR [c.1255 T > G, p.(Y419D)] and LDLRAP1 genes [c.604_605delTCinsA, p.(S202Tfs*2)]. The proband was found to be homozygous for the LDLR variant and heterozygous for the LDLRAP1 variant.
      Three of the proband's children were found to be double heterozygous for the LDLR/LDLRAP1 gene variant. While her other three children were heterozygous for the same single LDLR variant. Both variants were not previously reported. The variants segregation pattern correlated with the clinical picture and with the patient's lipid profile. FH severity was greater in the proband while her children did not show any clinical manifestations. The missense variant p.(Y419D) was found to be deleterious and clinically significant based on prediction identified by PolyPhen-2 and Proven. Molecular dynamics simulation was used to further analyze the effect of the variant p.(Y419D) on the structure and function of the LDLR protein. The secondary structure was investigated, as well as the solvent accessibility and stabilizing residues. The frameshift variant of the LDLRAP1 gene results in a truncated peptide that could affect the cellular internalization of LDLR/LDL complex.

      Conclusions

      The finding of the combined variants in LDLR/LDLRAP1 genes triggering a severe FH phenotype is essential to elaborate the spectrum of variants causing FH and to understand the genotype-phenotype correlation.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to Atherosclerosis
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • Cuchel M.
        • Bruckert E.
        • Ginsberg H.N.
        • Raal F.J.
        • Santos R.D.
        • Hegele R.A.
        • Kuivenhoven J.A.
        • Nordestgaard B.G.
        • Descamps O.S.
        • Steinhagen-Thiessen E.
        • Tybjærg- Hansen A.
        • Watts G.F.
        • Averna M.
        • Boileau C.
        • Borén J.
        • Catapano A.L.
        • Defesche J.C.
        • Hovingh G.K.
        • Humphries S.E.
        • Kovanen P.T.
        • Masana L.
        • Pajukanta P.
        • Parhofer K.G.
        • Ray K.K.
        • Stalenhoef A.F.
        • Stroes E.
        • Taskinen M.R.
        • Wiegman A.
        • Wiklund O.
        • Chapman M.J.
        • E.A.S.C.P.o.F
        Hypercholesterolaemia, Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society.
        Eur. Heart J. 2014; 35: 2146-2157
        • Al-Allaf F.A.
        • Coutelle C.
        • Waddington S.N.
        • David A.L.
        • Harbottle R.
        • Themis M.
        LDLR-Gene therapy for familial hypercholesterolaemia: problems, progress, and perspectives.
        Int. Arch. Med. 2010; 3: 36
        • Nordestgaard B.G.
        • Chapman M.J.
        • Humphries S.E.
        • Ginsberg H.N.
        • Masana L.
        • Descamps O.S.
        • Wiklund O.
        • Hegele R.A.
        • Raal F.J.
        • Defesche J.C.
        • Wiegman A.
        • Santos R.D.
        • Watts G.F.
        • Parhofer K.G.
        • Hovingh G.K.
        • Kovanen P.T.
        • Boileau C.
        • Averna M.
        • Borén J.
        • Bruckert E.
        • Catapano A.L.
        • Kuivenhoven J.A.
        • Pajukanta P.
        • Ray K.
        • Stalenhoef A.F.
        • Stroes E.
        • Taskinen M.R.
        • Tybjærg-Hansen A.
        • Panel E.A.S.C.
        Familial hypercholesterolaemia is underdiagnosed and undertreated in the general population: guidance for clinicians to prevent coronary heart disease: consensus statement of the European Atherosclerosis Society.
        Eur. Heart J. 2013; 34 (3478–3490a)
        • Sjouke B.
        • Hovingh G.K.
        • Kastelein J.J.
        • Stefanutti C.
        Homozygous autosomal dominant hypercholesterolaemia: prevalence, diagnosis, and current and future treatment perspectives.
        Curr. Opin. Lipidol. 2015; 26: 200-209
        • Harrison P.
        US prevalence of familial hypercholesterolemia higher than expected. News and perspective.
        Cardilogy. 2016; (March 14)
        • Austin M.A.
        • Hutter C.M.
        • Zimmern R.L.
        • Humphries S.E.
        Genetic causes of monogenic heterozygous familial hypercholesterolemia: a HuGE prevalence review.
        Am. J. Epidemiol. 2004; 160: 407-420
        • Al-Allaf F.A.
        • Athar M.
        • Abduljaleel Z.
        • Bouazzaoui A.
        • Taher M.M.
        • Own R.
        • Al- Allaf A.F.
        • AbuMansour I.
        • Azhar Z.
        • Ba-Hammam F.A.
        • Abalkhail H.
        • Alashwal A.
        Identification of a novel nonsense variant c.1332dup, p. (D445*) in the LDLR gene that causes familial hypercholesterolemia.
        Hum. Genome Var. 2014; 1: 14021
        • Al-Allaf F.A.
        • Athar M.
        • Abduljaleel Z.
        • Taher M.M.
        • Khan W.
        • Ba-Hammam F.A.
        • Abalkhail H.
        • Alashwal A.
        Next generation sequencing to identify novel genetic variants causative of autosomal dominant familial hypercholesterolemia associated with increased risk of coronary heart disease.
        Gene. 2015; 565: 76-84
        • Al-Allaf F.A.
        • Alashwal A.
        • Abduljaleel Z.
        • Taher M.M.
        • Siddiqui S.S.
        • Bouazzaoui A.
        • Abalkhail H.
        • Aun R.
        • Al-Allaf A.F.
        • AbuMansour I.
        • Azhar Z.
        • Ba-Hammam F.A.
        • Khan W.
        • Athar M.
        Identification of a recurrent frameshift mutation at the LDLR exon 14 (c.2027delG, p. (G676Afs*33)) causing familial hypercholesterolemia in Saudi Arab homozygous children.
        Genomics. 2016; 107: 24-32
        • Al-Allaf F.A.
        • Alashwal A.
        • Abduljaleel Z.
        • Taher M.M.
        • Bouazzaoui A.
        • Abalkhail H.
        • Al-Allaf A.F.
        • Athar M.
        Compound heterozygous LDLR variant in severely affected familial hypercholesterolemia patient.
        Acta Biochim. Pol. 2017; 64: 75-79
        • Al-Allaf F.A.
        • Nazar F.A.H.
        • Alnefaie M.
        • Almaymun A.
        • Rashidi O.M.
        • Alhabib K.
        • Alnouri F.
        • Alama M.N.
        • Athar M.
        • Awan Z.
        The spectrum of familial hypercholesterolemia (FH) in Saudi Arabia: prime time for patient FH registry, open cardiovasc.
        Med. J. 2017; 11: 66-75
        • Alharbi K.K.
        • Kashour T.S.
        • Al-Hussaini W.
        • Nbaheen M.S.
        • Hasanato R.M.
        • Mohamed S.
        • Tamimi W.
        • Khan I.A.
        Screening for genetic mutations in LDLR gene with familial hypercholesterolemia patients in the Saudi population.
        Acta Biochim. Pol. 2015; 62: 559-562
        • Al-Ashwal A.
        • Alnouri F.
        • Sabbour H.
        • Al-Mahfouz A.
        • Al-Sayed N.
        • Razzaghy- Azar M.
        • Al-Allaf F.
        • Al-Waili K.
        • Banerjee Y.
        • Genest J.
        • Santos R.D.
        • Al-Rasadi K.
        Identification and treatment of patients with homozygous familial hypercholesterolaemia: information and recommendations from a Middle East advisory panel.
        Curr. Vasc. Pharmacol. 2015; 13: 759-770
        • El-Mouzan M.I.
        • Al-Salloum A.A.
        • Al-Herbish A.S.
        • Qurachi M.M.
        • Al-Omar A.A.
        Regional variations in the prevalence of consanguinity in Saudi Arabia.
        Saudi Med. J. 2007; 28: 1881-1884
        • Tadmouri G.O.
        • Nair P.
        • Obeid T.
        • Al Ali M.T.
        • Al Khaja N.
        • Hamamy H.A.
        Consanguinity and reproductive health among Arabs.
        Reprod. Health. 2009; 6: 17
        • Harada-Shiba M.
        • Tajima S.
        • Yokoyama S.
        • Miyake Y.
        • Kojima S.
        • Tsushima M.
        • Kawakami M.
        • Yamamoto A.
        Siblings with normal LDL receptor activity and severe hypercholesterolemia.
        Arterioscler. Thromb. 1992; 12: 1071-1078
        • Garcia C.K.
        • Wilund K.
        • Arca M.
        • Zuliani G.
        • Fellin R.
        • Maioli M.
        • Calandra S.
        • Bertolini S.
        • Cossu F.
        • Grishin N.
        • Barnes R.
        • Cohen J.C.
        • Hobbs H.H.
        Autosomal recessive hypercholesterolemia caused by mutations in a putative LDL receptor adaptor protein.
        Science. 2001; 292: 1394-1398
        • Pisciotta L.
        • Priore Oliva C.
        • Pes G.M.
        • Di Scala L.
        • Bellocchio A.
        • Fresa R.
        • Cantafora A.
        • Arca M.
        • Calandra S.
        • Bertolini S.
        Autosomal recessive hypercholesterolemia (ARH) and homozygous familial hypercholesterolemia (FH): a phenotypic comparison.
        Atherosclerosis. 2006; 188: 398-405
        • Harada K.
        • Miyamoto Y.
        • Morisaki H.
        • Ohta N.
        • Yamanaka I.
        • Kokubo Y.
        • Makino H.
        • Harada-Shiba M.
        • Okayama A.
        • Tomoike H.
        • Okamura T.
        • Tomonori O.
        • Saito Y.
        • Yoshimasa Y.
        • Morisaki T.
        A novel Thr56Met mutation of the autosomal recessive hypercholesterolemia gene associated with hypercholesterolemia.
        J. Atherosclerosis Thromb. 2010; 17: 131-140
        • Tada H.
        • Kawashiri M.A.
        • Ohtani R.
        • Noguchi T.
        • Nakanishi C.
        • Konno T.
        • Hayashi K.
        • Nohara A.
        • Inazu A.
        • Kobayashi J.
        • Mabuchi H.
        • Yamagishi M.
        A novel type of familial hypercholesterolemia: double heterozygous mutations in LDL receptor and LDL receptor adaptor protein 1 gene.
        Atherosclerosis. 2011; 219: 663-666
        • Risk of fatal coronary heart disease in familial hypercholesterolaemia
        Scientific steering committee on behalf of the Simon Broome register group.
        BMJ. 1991; 303: 893-896
        • Kumar P.
        • Henikoff S.
        • Ng P.C.
        Predicting the effects of coding non-synonymous variants on protein function using the SIFT algorithm.
        Nat. Protoc. 2009; 4: 1073-1081
        • Edrees B.M.
        • Athar M.
        • Al-Allaf F.A.
        • Taher M.M.
        • Khan W.
        • Bouazzaoui A.
        • Al- Harbi N.
        • Safar R.
        • Al-Edressi H.
        • Alansary K.
        • Anazi A.
        • Altayeb N.
        • Ahmed M.A.
        • Abduljaleel Z.
        Next-generation sequencing for molecular diagnosis of autosomal recessive polycystic kidney disease.
        Gene. 2016; 591: 214-226
        • Brooks B.R.
        • Brooks C.L.
        • Mackerell A.D.
        • Nilsson L.
        • Petrella R.J.
        • Roux B.
        • Won Y.
        • Archontis G.
        • Bartels C.
        • Boresch S.
        • Caflisch A.
        • Caves L.
        • Cui Q.
        • Dinner A.R.
        • Feig M.
        • Fischer S.
        • Gao J.
        • Hodoscek M.
        • Im W.
        • Kuczera K.
        • Lazaridis T.
        • Ma J.
        • Ovchinnikov V.
        • Paci E.
        • Pastor R.W.
        • Post C.B.
        • Pu J.Z.
        • Schaefer M.
        • Tidor B.
        • Venable R.M.
        • Woodcock H.L.
        • Wu X.
        • Yang W.
        • York D.M.
        • Karplus M.
        CHARMM: the biomolecular simulation program.
        J. Comput. Chem. 2009; 30: 1545-1614
        • Hess B.
        • Kutzner C.
        • van der Spoel D.
        • Lindahl E.
        GROMACS 4: algorithms for highly efficient, load-balanced, and scalable molecular simulation.
        J. Chem. Theor. Comput. 2008; 4: 435-447
        • Jorgensen W.L.
        • Chandrasekhar J.
        • Madura J.D.
        • Impey R.W.
        • Kleinn M.L.
        Comparison of simple potential functions for simulating liquid water.
        J. Chem. Phys. 1983; 79: 926-935
        • Pires D.E.V.
        • Ascher D.B.
        • Blundell T.L.
        DUET: a server for predicting effects of mutations on protein stability via an integrated computational approach.
        Nucleic Acids Res. 2014; 42: W314-W319
        • Abecasis G.R.
        • Auton A.
        • Brooks L.D.
        • DePristo M.A.
        • Durbin R.M.
        • Handsaker R.E.
        • Kang H.M.
        • Marth G.T.
        • McVean G.A.
        • Consortium G.P.
        An integrated map of genetic variation from 1,092 human genomes.
        Nature. 2012; 491: 56-65
        • Forbes S.A.
        • Tang G.
        • Bindal N.
        • Bamford S.
        • Dawson E.
        • Cole C.
        • Kok C.Y.
        • Jia M.
        • Ewing R.
        • Menzies A.
        • Teague J.W.
        • Stratton M.R.
        • Futreal P.A.
        COSMIC (the Catalogue of Somatic Mutations in Cancer): a resource to investigate acquired mutations in human cancer.
        Nucleic Acids Res. 2010; 38: D652-D657
        • Flicek P.
        • Amode M.R.
        • Barrell D.
        • Beal K.
        • Billis K.
        • Brent S.
        • Carvalho-Silva D.
        • Clapham P.
        • Coates G.
        • Fitzgerald S.
        • Gil L.
        • Girón C.G.
        • Gordon L.
        • Hourlier T.
        • Hunt S.
        • Johnson N.
        • Juettemann T.
        • Kähäri A.K.
        • Keenan S.
        • Kulesha E.
        • Martin F.J.
        • Maurel T.
        • McLaren W.M.
        • Murphy D.N.
        • Nag R.
        • Overduin B.
        • Pignatelli M.
        • Pritchard B.
        • Pritchard E.
        • Riat H.S.
        • Ruffier M.
        • Sheppard D.
        • Taylor K.
        • Thormann A.
        • Trevanion S.J.
        • Vullo A.
        • Wilder S.P.
        • Wilson M.
        • Zadissa A.
        • Aken B.L.
        • Birney E.
        • Cunningham F.
        • Harrow J.
        • Herrero J.
        • Hubbard T.J.
        • Kinsella R.
        • Muffato M.
        • Parker A.
        • Spudich G.
        • Yates A.
        • Zerbino D.R.
        • Searle S.M.
        Ensembl 2014.
        Nucleic Acids Res. 2014; 42: D749-D755
        • Soufi M.
        • Rust S.
        • Walter M.
        • Schaefer J.R.
        A combined LDL receptor/LDL receptor adaptor protein 1 mutation as the cause for severe familial hypercholesterolemia.
        Gene. 2013; 521: 200-203
        • Fahed A.C.
        • Khalaf R.
        • Salloum R.
        • Andary R.R.
        • Safa R.
        • El-Rassy I.
        • Moubarak E.
        • Azar S.T.
        • Bitar F.F.
        • Nemer G.
        Variable expressivity and co-occurrence of LDLR and LDLRAP1 mutations in familial hypercholesterolemia: failure of the dominant and recessive dichotomy.
        Mol. Genet. Genomic Med. 2016; 4: 283-291
        • Klose G.
        • Laufs U.
        • März W.
        • Windler E.
        Familial hypercholesterolemia: developments in diagnosis and treatment.
        Dtsch Arztebl Int. 2014; 111: 523-529
        • Mollaki V.
        • Progias P.
        • Drogari E.
        Novel LDLR variants in patients with familial hypercholesterolemia: in silico analysis as a tool to predict pathogenic variants in children and their families.
        Ann. Hum. Genet. 2013; 77: 426-434