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Detection of biotinidase gene mutations in Turkish patients ascertained by newborn and family screening

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Abstract

The incidence of biotinidase deficiency in Turkey is currently one of the highest in the world. To expand upon the information about the biotinidase gene (BTD) variations in Turkish patients, we conducted a mutation screening in a large series (n = 210) of probands with biotinidase deficiency, using denaturing high-performance liquid chromatography and direct DNA sequencing. The putative effects of novel mutations were predicted by computational program. Twenty-six mutations, including six novels (p.C143F, p.T244I, c.1212-1222del11, c.1320delG, p.V457L, p.G480R) were identified. Nine of the patients were symptomatic at the initial clinical assessment with presentations of seizures, encephalopathy, and lactic acidemia. The most common mutation in this group of symptomatic patients was c.98-104 del7ins3. Among the screened patients, 72 have partial and 134 have profound biotinidase deficiency (BD) of which 106 are homozygous for BTD mutations. The common mutations (p.R157H, p.D444H, c.98-104del7ins3, p.T532M) cumulatively accounted for 72.3 % of all the mutant alleles in the Turkish population.

Conclusion: The identification of common mutations and hot spot regions of the BTD gene in Turkish patients is important for mutation screening in the Turkish population and helps to ascertain carriers, may have impact on genetic counseling and implementing prevention programs.

What is Known

• The screened group is one of the largest series (n = 210) of BD probands in childhood and provides reliable information about the BTD gene mutation spectrum in the Turkish population.

What is New

• This study adds six novel mutations, their phenotypic presentations and putative effects to the literature.

• Seventeen of the detected mutant alleles caused early symptoms.

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Abbreviations

ACC-1:

Acetyl-CoA carboxylase-1

ACC-2:

Acetyl-CoA carboxylase-2

BD:

Biotinidase deficiency

BTD:

Biotinidase enzyme

dHPLC:

Denaturing high-performance liquid chromatography

MCC:

Methylcrotonyl-CoA carboxylase

PC:

Pyruvate carboxylase

PCC:

Propionyl-CoA carboxylase

PCR:

Polymerase chain reaction

PS-DVB:

Polystyrene-divinyl-benzene

TEAA:

Triethylammonium acetate

References

  1. Al-Shamsi A, Hertecant JL, Al-Hamad S, Souid AK, Al-Jasmi F (2014) Mutation spectrum and birth prevalence of inborn errors of metabolism among Emiratis. Sultan Qaboos Univ Med J 14(1):42–49

    Article  Google Scholar 

  2. Anonymous (2011) Newborn screening programs in Turkey. Ministry of Health, Health of mother-child and family plannig general managment

  3. Baumgartner ER, Suormala T (2000) Biotin responsive multiple carboxylase deficiency. In: Fernandes J, Saudubray JM, Van den Berghe G (eds) Inborn metabolic diseases: diagnosis and treatment, 3rd edn. Springer, New York, p 276

    Chapter  Google Scholar 

  4. Baykal T, Gokcay G, Gokdemir Y, Demir F, Seckin Y, Demirkol M, Jensen K, Wolf B (2005) Asymptomatic adults and older siblings with biotinidase deficiency ascertained by family studies of index cases. J Inherit Metab Dis 28(6):903–912. doi:10.1007/s10545-005-0161-3

    Article  CAS  PubMed  Google Scholar 

  5. Chedrawi AK, Ali A, Al Hassnan ZN, Faiyaz-Ul-Haque M, Wolf B (2008) Profound biotinidase deficiency in a child with predominantly spinal cord disease. J Child Neurol 23:1043–1048. doi:10.1177/0883073808318062

    Article  PubMed  Google Scholar 

  6. Cole H, Reynolds TR, Buck GB, Lockyer JM, Denson T, Spence JE, Hymes J, Wolf B (1994) Human serum biotinidase: cDNA cloning, sequence and characterization. J Biol Chem 269:6566–6570

    CAS  PubMed  Google Scholar 

  7. Cowan TM, Blitzer M, Wolf B (2010) Technical standards and guidelines for the diagnosis of biotinidase deficiency. Genet Med 12(7):464–470. doi:10.1097/GIM.0b013e3181e4cc0f

    Article  CAS  PubMed  Google Scholar 

  8. Dobrowolski SF, Angeletti J, Banas RA, Naylor EW (2003) Real time PCR assays to detect common mutations the biotinidase gene and application of mutational analysis to newborn screening for biotinidase deficiency. Mol Genet Metab 78:100–107. doi:10.1016/S1096-7192(02)00231-7

    Article  CAS  PubMed  Google Scholar 

  9. Hernandez-Vazquez A, Wolf B, Pindolia K, Ortega-Cuellar D, Hernandez-Gonzalez R, Heredia-Antunez A, Ibarra-Gonzalez I, Velazquez-Arellano A (2013) Biotinidase knockout mice show cellular energy deficit and altered carbon metabolism gene expression similar to that of nutritional biotin deprivation: clues for the pathogenesis in the human inherited disorder. Mol Genet Metab 110:248–254. doi:10.1016/j.ymgme.2013.08.018

    Article  CAS  PubMed  Google Scholar 

  10. Knight HC, Reynolds TR, Meyers GA, Pomponio RJ, Buck GA, Wolf B (1998) Structure of human biotinidase gene. Mamm Genome 9:327–330

    Article  CAS  PubMed  Google Scholar 

  11. Küry S, Ramaekers V, Bezieau S, Wolf B (2012) Clinical utility gene card for: biotinidase deficiency. Eur J Hum Genet. doi:10.1038/ejhg.2012.28

    Google Scholar 

  12. Laszlo A, Schuler EA, Sallay E, Endreffy E, Somagyi C, Varkonyi A, Havass Z, Jensen K, Wolf B (2003) Neonatal screening for biotinidase deficiency in Hungary: clinical, biochemical and molecular studies. J Inherit Metab Dis 26:693–698

    Article  CAS  PubMed  Google Scholar 

  13. Li H, Spencer L, Nahhas F, Miller J, Fribley A, Feldman G, Conway R, Wolf B (2014) Novel mutations causing biotinidase deficiency in individuals identified by newborn screening in Michigan including an unique intronic mutation that alters mRNA expression of the biotinidase gene. Mol Genet Metab 112(3):242–246. doi:10.1016/j.ymgme.2014.04.002

    Article  CAS  PubMed  Google Scholar 

  14. Möslinger D, Stockler-Ipsiroglu S, Scheibenreiter S, Tiefenthaler M, Mühl A, Seidl R, Strobl W, Plecko B, Suormala T, Baumgartner ER (2001) Clinical and neuropsychological outcome in 33 patients with biotinidase deficiency ascertained by nationwide newborn screening and family studies in Austria. Eur J Pediatr 160:277–282

    Article  PubMed  Google Scholar 

  15. Möslinger D, Mühl A, Suormala T, Baumgartner R, Stockler-Ipsiroglu S (2003) Molecular characterisation and neuropsychological outcome of 21 patients with profound biotinidase deficiency detected by newborn screening and family studies. Eur J Pediatr 162:46–49. doi:10.1007/s00431-003-1351-3

    Article  Google Scholar 

  16. Mühl A, Möslinger D, Item CB, Stockler-Ipsiroglu S (2001) Molecular characterization of 34 patients with biotinidase deficiency ascertained by newborn screening and family investigation. Eur J Hum Genet 9:237–243

    Article  PubMed  Google Scholar 

  17. Norrgard KJ, Pomponio RJ, Swango KL, Hymes J, Reynolds TR, Buck GA, Wolf B (1997) Mutation (Q456H) is the most common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States. Biochem Mol Med 61(1):22–27

    Article  CAS  PubMed  Google Scholar 

  18. Norrgard KJ, Pomponio RJ, Swango KL, Hymes J, Reynolds T, Buck GA, Wolf B (1998) Double mutation [A171T and D444H] is a common cause of profound biotinidase deficiency in children ascertained by newborn screening in the United States. Hum Mutat 11:410. doi:10.1002/(SICI)1098-1004(1998)11:5<410::AID-HUMU10>3.0.CO;2-8

    Article  CAS  PubMed  Google Scholar 

  19. Norrgard KJ, Pomponio RJ, Hymes J, Wolf B (1999) Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediatr Res 46 (1):2 0–27

  20. Ohlsson A, Guthenberg C, Holme E, von Dobeln U (2010) Profound biotinidase deficiency; a rare disease among native Swedes. J Inherit Metab Dis 33(Suppl3):175–180. doi:10.1007/s10545-010-9065-y

    Article  Google Scholar 

  21. Pace HC, Brenner C (2001) The nitrilase superfamily: classification, structure and function. Genome Biol 2:1.1–1.9

    Article  Google Scholar 

  22. Pindolia K, Jensen K, Wolf B (2007) Three dimensional structure of human biotinidase: computer modeling and functional correlations. Mol Genet Metab 92:13–22. doi:10.1016/j.ymgme.2007.04.013

    Article  CAS  PubMed  Google Scholar 

  23. Pindolia K, Jordan M, Wolf B (2010) Analysis of mutations causing biotinidase deficiency. Hum Mut 31(9):983–991. doi:10.1002/humu.21303

    Article  CAS  PubMed  Google Scholar 

  24. Pindolia K, Jordan M, Guo C, Matthews N, Mock DM, Strovel E, Blitzer M, Wolf B (2011) Development and characterization of a mouse with profound biotinidase deficiency: a biotin-responsive neurocutaneous disorder. Mol Genet Metab 102:161–169. doi:10.1016/j.ymgme.2010.10.005

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  25. Pindolia K, Chen J, Cardwell C, Cui X, Chopp M, Wolf B (2012) Neurological deficits in mice with profound biotinidase deficiency are associated with demylination and axonal degeneration. Neurobiol Dis 47:428–435. doi:10.1016/j.nbd.2012.04.016

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  26. Pomponio RJ, Hymes J, Reynolds TR, Meyers GA, Fleischhauer K, Buck GA, Wolf B (1997) Mutations in the human biotinidase gene that cause profound biotinidase deficiency in symptomatic children: molecular, biochemical, and clinical analysis. Pediatr Res 42:840–848. doi:10.1203/00006450-199712000-00020

    Article  CAS  PubMed  Google Scholar 

  27. Pomponio RJ, Norrgard KJ, Hymes J, Reynolds TR, Reynolds TR, Buck GA, Baumgartner R, Suormala T, Wolf B (1997) Arg538 to Cys mutation in a CpG dinucleotide of the human biotinidase gene is the second most common cause of biotinidase deficiency in symptomatic children with biotinidase deficiency. Hum Genet 99:506–512

    Article  CAS  PubMed  Google Scholar 

  28. Pomponio RJ, Yamaguchi A, Arashima S, Hymes J, Wolf B (1998) Mutation in a putative glycosylation site (N489T) of biotinidase is the only known Japanese child with biotinidase deficiency. Mol Genet Metab 64:152–154. doi:10.1006/mgme.1998.2706

    Article  CAS  PubMed  Google Scholar 

  29. Pomponio RJ, Coskun T, Demirkol M, Tokatli A, Ozalp I, Hüner G, Baykal T, Wolf B (2000) Novel mutations cause biotinidase deficiency in Turkish children. J Inherit Metab Dis 23:120–128

    Article  CAS  PubMed  Google Scholar 

  30. Procter M, Wolf B, Crockett DK, Mao R (2013) The biotinidase gene variants registry: a paradigm public database. G3 (Bethesda) 3(4):727–731. doi:10.1534/g3.113.005835

    Article  CAS  Google Scholar 

  31. Raha S, Udani V (2011) Biotinidase deficiency presenting as recurrent myelopathy in a 7-year-old boy and a review of the literature. Pediatr Neurol 45:261–264. doi:10.1016/j.pediatrneurol.2011.06.010

    Article  PubMed  Google Scholar 

  32. Sarafoglou K, Bentler K, Gaviglio A, Redlinger-Grosse K, Anderson C, McCann M, Bloom B, Babovic-Vuksanovic D, Gavrilov D, Berry SA (2009) High incidence of profound biotinidase deficiency detected in newborn screening blood spots in the Somalian population in Minnesota. J Inherit Metab Dis 32(Suppl1):169–173. doi:10.1007/s10545-009-1135-7

    Article  CAS  Google Scholar 

  33. Sivri HS, Genç GA, Tokatli A, Dursun A, Coşkun T, Aydin HI, Sennaroğlu L, Belgin E, Jensen K, Wolf B (2007) Hearing loss in biotinidase deficiency: genotype-phenotype correlation. J Pediatr 150 (4):4 39–442. DOI: 10.1016/j.jpeds.2007.01.036

  34. Stanley CM, Hymes J, Wolf B (2004) Identification of alternatively spliced human biotinidase mRNAs and putative localization of endogenous biotinidase. Mol Genet Metab 81(4):300–312. doi:10.1016/j.ymgme.2003.12.006

    Article  CAS  PubMed  Google Scholar 

  35. Suzuki Y, Yang X, Aoki Y, Kure S, Matsubara Y (2005) Mutations in the holocarboxylase synthetase gene HLCS. Hum Mutat 26(4):285–290. doi:10.1002/humu.20204

    Article  CAS  PubMed  Google Scholar 

  36. Swango KL, Demirkol M, Huner G, Pronicka E, Sykut-Cegielska J, Schulze A, Wolf B (1998) Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. Hum Genet 102:571–575

    Article  CAS  PubMed  Google Scholar 

  37. Swango KL, Wolf B (2001) Conservation of biotindase in mammals and identification of the putative biotinidase gene in Drosophila melanogaster. Mol Genet Metab 74:492–499. doi:10.1006/mgme.2001.3244

    Article  CAS  PubMed  Google Scholar 

  38. Thodi G, Schulpis KH, Molou E, Georgiou V, Loukas YL, Dotsikas Y, Papadopoulos K, Biti S (2013) High incidence of partial biotinidase deficiency cases in newborns of Greek origin. Gene 524:361–362. doi:10.1016/j.gene.2013.04.059

    Article  CAS  PubMed  Google Scholar 

  39. Winchester S, Singh PK, Mikati MA (2013) Ataxia. Handb Clin Neurol 112:1213–1217. doi:10.1016/B978-0-444-52910-7.00043-X

    Article  PubMed  Google Scholar 

  40. Wolf B, Heard GS (1990) Screening for biotinidase deficiency in newborns: worldwide experience. Pediatrics 85:512–517

    CAS  PubMed  Google Scholar 

  41. Wolf B (1993) Biotinidase deficiency, In: Pagon RA, Bird TD, Dolan CR, Stephens K, (eds). GeneReviews

  42. Wolf B, Pomponio RJ, Norrgard KJ, Lott IT, Baumgartner ER, Suormala T, RaemarkersVTh CT, Tokatlı A, Ozalp I, Hymes J (1998) Delayed-onset profound biotinidase deficiency. J Pediatr 132:362–365. doi:10.1016/S0022-3476(98)70464-0

    Article  CAS  PubMed  Google Scholar 

  43. Wolf B, Jensen K, Huner G, Demirkol M, Baykal T, Divry P, Rolland MO, Perez-Cerdá C, Ugarte M, Straussberg R, Basel-Vanagaite L, Baumgartner ER, Suormala T, Scholl S, Das AM, Schweitzer S, Pronicka E, Sykut-Cegielska J (2002) Seventeen novel mutations that cause profound biotinidase deficiency. Mol Genet Metab 77:108–111. doi:10.1016/S1096-7192(02)00149-X

    Article  CAS  PubMed  Google Scholar 

  44. Wolf B, Jensen KP, Barshop B, Blitzer M, Carlson M, Goudie DR, Gokcay GH, Demirkol M, Baykal T, Demir F, Quary S, Shih LY, Pedro HF, Chen TH, Slonim AE (2005) Biotinidase deficiency: novel mutations and their biochemical and clinical correlates. Hum Mutat 25:413. doi:10.1002/humu.9329

    Article  PubMed  Google Scholar 

  45. Wolf B, Jensen K (2005) Evolutionary conservation of biotinidase: implications for the enzyme’s structure and subcellular localization. Mol Genet Metab 86:44–50. doi:10.1016/j.ymgme.2005.07.011

    Article  CAS  PubMed  Google Scholar 

  46. Wolf B (2010) Clinical issues and frequent questions about biotinidase deficiency. Mol Genet Metab 100:6–13. doi:10.1016/j.ymgme.2010.01.003

    Article  CAS  PubMed  Google Scholar 

  47. Wolf B (2011) The neurology of biotinidase deficiency. Mol Genet Metab 104:27–34. doi:10.1016/j.ymgme.2011.06.001

    Article  CAS  PubMed  Google Scholar 

  48. Ye J, Han LS, Qui WJ, Zhang HW, Zhang YF, Gao XL, Wang Y, Gu XF (2009) Diagnosis, treatment, follow-up and gene mutation analysis in four Chinese children with biotinidase deficiency. J Inherit Metab Dis 32(Suppl1):295–302. doi:10.1007/s10545-009-1238-1

    Article  Google Scholar 

  49. Zempleni J, Kuroishi T (2012) Biotin. Adv Nutr 3(2):213–214. doi:10.3945/an.111.001305

    Article  PubMed Central  PubMed  Google Scholar 

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Acknowledgments

We thank to Dr. Şefayet Karaca for the scientific contribution. We would like to thank to Esin Göksun and Ayşegül Ozantürk, and to the members of DNA Bank at Hacettepe University, for biobanking assistance. We are grateful to the patients and their families for their collaboration.

This work was funded by a grant from State Planning Organization of Turkey (Project number: DPT2006K1206400603).

Conflict of interest

The authors declare that they have no conflict of interest.

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Authors and Affiliations

  1. Faculty of Science and Arts, Department of Biology, Aksaray University, Aksaray, Turkey

    Mehmet Karaca

  2. Faculty of Medicine, Department of Pediatrics, Metabolism Unit, Hacettepe University, Ankara, Turkey

    Mehmet Karaca, Rıza Köksal Özgül, Özlem Ünal, Didem Yücel-Yılmaz, Mustafa Kılıç, Burcu Hişmi, Ayşegül Tokatlı, Turgay Coşkun, Ali Dursun & Hatice Serap Sivri

  3. Institute of Child Health, Hacettepe University, Ankara, Turkey

    Rıza Köksal Özgül

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  1. Mehmet Karaca
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  2. Rıza Köksal Özgül
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Correspondence to Hatice Serap Sivri.

Additional information

Communicated by Beat Steinmann

Revisions received: 07 February 2015/16 February 2015

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Karaca, M., Özgül, R.K., Ünal, Ö. et al. Detection of biotinidase gene mutations in Turkish patients ascertained by newborn and family screening. Eur J Pediatr 174, 1077–1084 (2015). https://doi.org/10.1007/s00431-015-2509-5

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  • DOI: https://doi.org/10.1007/s00431-015-2509-5

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