HGNC Approved Gene Symbol: BTD
SNOMEDCT: 8808004; ICD10CM: D81.810;
Cytogenetic location: 3p25.1 Genomic coordinates (GRCh38) : 3:15,601,361-15,722,516 (from NCBI)
| Location | Phenotype |
Phenotype MIM number |
Inheritance |
Phenotype mapping key |
|---|---|---|---|---|
| 3p25.1 | Biotinidase deficiency | 253260 | Autosomal recessive | 3 |
Serum biotinidase (BTD; EC 3.5.1.12) catalyzes the hydrolysis of biocytin, a normal product of biotin-dependent carboxylase degradation, to biotin and lysine. The process results in the regeneration of free biotin. Biotin is an essential water-soluble vitamin and is the coenzyme for 4 carboxylases necessary for normal metabolism in humans: pyruvate carboxylase (PCC; 608786), propionyl-CoA carboxylase (PCCA; 232000), alpha-methylcrotonyl-CoA carboxylase (see MCCC1; 609010), and acetyl-CoA carboxylase (ACACA; 200350) (summary by Cole et al., 1994).
Pomponio et al. (1997) stated that biotinidase has also been shown to have biotinyl-transferase activity.
Cole et al. (1994) cloned and sequenced a cDNA corresponding to the BTD gene from a human hepatic cDNA library. The deduced 543-amino acid protein has a molecular mass of approximately 57 kD and contains 6 potential N-linked glycosylation sites. Northern blot analysis detected BTD mRNA in human heart, brain, placenta, liver, lung, skeletal muscle, kidney, and pancreas.
Knight et al. (1998) determined that the BTD gene contains 4 exons and spans at least 23 kb.
Using fluorescence in situ hybridization, Cole et al. (1994) mapped the BTD gene to chromosome 3p25.
In 10 of 25 patients with biotinidase deficiency (253260), Pomponio et al. (1995) identified an allele with a 7-bp deletion and a 3-bp insertion in the BTD gene (609019.0001).
In 37 symptomatic children (30 index cases and 7 sibs) with profound biotinidase deficiency, Pomponio et al. (1997) identified 21 mutations in the BTD gene. The 2 most common mutations were the del7/ins3 mutation and R538C (609019.0003); these 2 mutations were found in 31 of 60 alleles (52%), whereas the remainder of the alleles were accounted for by the 19 other unique mutations.
In 2 unrelated asymptomatic adults with biotinidase deficiency who were diagnosed because their children were identified by newborn screening, Wolf et al. (1997) found homozygous mutations in the BTD gene (609019.0005 and 609019.0006). Wolf et al. (1997) concluded that epigenetic factors may protect some enzyme-deficient individuals from developing symptoms.
Pomponio et al. (2000) identified mutations in the BTD gene (see, e.g., 609019.0007; 609019.0010; 609019.0011) in Turkish children with biotinidase deficiency identified both clinically and by newborn screening.
Carvalho et al. (2019) reported molecular and serum enzyme testing results in 14 Brazilian children with biotinidase deficiency who were identified by newborn screening. Nine novel mutations were identified, including 2 deletions and 7 missense mutations. Seven of the mutations were found in exon 4, which encodes the C terminus. Among the missense mutations that were identified in homozygous state, F361V (609019.0012) led to partial biotinidase deficiency in 2 unrelated patients, and A534V (609019.0013) led to profound biotinidase deficiency in 1 patient. The previously reported D444H mutation (609019.0005) was found in compound heterozygosity in 7 patients; 5 of the patients had partial biotinidase deficiency, including one with compound heterozygosity for A534V and one with compound heterozygosity for F361V, and 2 of the patients had possible partial biotinidase deficiency.
Hernandez-Vazquez et al. (2013) studied the metabolic features of 3-week-old Btd-null mice that had been fed a biotin-deficient diet for 5 days. The mice showed no phenotypic alterations characteristic of biotinidase deficiency, such as seizures, hypotonia, ataxia, or hair or skin abnormalities. Liver samples from the mice showed decreased cellular energy, with an increase in the AMP/ATP ratio and an increase in phosphorylation of AMP-activated protein kinase (AMPK; see 602739). There was inhibition of the signaling protein mTOR (601231), which is a driver of protein synthesis and growth. The transcripts of several central carbon metabolism genes were also changed: GCK (138079) and FASN (600212) were increased, whereas those of PCK1 (614168) and CPT1 (600528) were decreased. The mice also showed increased serum levels of free fatty acids, decreased levels of blood glucose, and increased insulin sensitivity. These findings indicated a severe energy deficit and altered energy metabolism in the absence of adequate biotin.
In 10 of 25 patients with biotinidase deficiency (253260), Pomponio et al. (1995) identified an allele with a 7-bp deletion and a 3-bp insertion (98-104del7ins3), immediately 3-prime to a 12-bp polypyrimidine sequence in the BTD gene. The deletion/insertion resulted in a frameshift that was predicted to terminate with a stop codon at amino acid 68, resulting in a truncated protein with an amino acid sequence different from that of biotinidase; the other allele contained the normal sequence. Three other patients were homozygous for the mutation. These 3 patients lacked crossreacting material to antibodies prepared against normal human serum biotinidase. The parents of 1 of the 3 patients were first cousins and those of a second were third cousins, whereas the parents of the third patient were not consanguineous. Racial and ethnic diversity and worldwide distribution of the patients studied suggested that the relatively high frequency of the mutation did not arise through a founder effect, and the authors suggested that it was a mutation hotspot.
Gordon (1996), who referred to the mutation as arising through an indel (insertion/deletion) event, questioned the 'hotspot' hypothesis and suggested that, like the delF508 mutation (219700.0001) for cystic fibrosis, this may be a very ancient mutation.
In a child with profound biotinidase deficiency (253260), Pomponio et al. (1996) identified homozygosity for a 15-bp deletion/11-bp insertion mutation within exon D (nucleotides 1059-1359 of the sequence reported by Cole et al. (1994)) of the BTD gene. The mutation resulted in a frameshift predicted to terminate the polypeptide prematurely. The authors proposed 2 possible mechanisms to account for this mutation, both of which involved formation of a quasipalindromic structure in the replicating DNA strands.
In 10 of 30 symptomatic children with profound biotinidase deficiency (253260), Pomponio et al. (1997) identified a 1612C-T transition in a CpG dinucleotide in exon D of the BTD gene, resulting in an arg538-to-cys (R538C) substitution. Five of the patients were compound heterozygous for this mutation and a deletion/insertion mutation (609019.0001). There was no detectable biotinidase protein in sera of homozygous children, and the authors suggested that the R538C mutation results in abnormal disulfide bond formation, rapid degradation of the aberrant enzyme, and failure to secrete the mutant enzyme from the cells into the blood. Pomponio et al. (1997) reported that the R538C mutation is the second most common mutation causing biotinidase deficiency.
In 2 unrelated individuals with profound biotinidase deficiency (253260), Pomponio et al. (1997) identified a 100G-A transition in the BTD gene, located 57 bases downstream of the authentic splice acceptor site in exon B, resulting in a gly34-to-ser (G34S) substitution. The transition also generated a 3-prime splice acceptor site. The sequence of the PCR-amplified cDNA from the homozygous child revealed that all the product was shorter than that of normal individuals and was the result of aberrant splicing. The aberrantly spliced transcript lacks 57 nucleotides, including a second in-frame ATG, that encode most of the putative signal peptide and results in an in-frame deletion of 19 amino acids. The mutation resulted in failure to secrete the aberrant protein into the blood. This was the first reported example in which a point mutation creates a cryptic 3-prime splice acceptor site motif that is used preferentially over the upstream authentic splice site. Pomponio et al. (1997) stated that preferential usage of the downstream splice site was not consistent with the 5-prime-to-3-prime scanning model of RNA splicing, but was consistent with the exon definition model.
In an asymptomatic man with biotinidase deficiency (253260) who was diagnosed because his affected child was identified by newborn screening, Wolf et al. (1997) identified a homozygous allelic double missense mutation in the BTD gene: a 511G-A transition, resulting in an ala171-to-thr (A171T) substitution, which had been described by Cole et al. (1994), and a 1330G-C transversion, resulting in an asp444-to-his (D444H) substitution, which had been described by Norrgard et al. (1996). The daughter had the same genotype; the parents of the father and his wife were heterozygous for this doubly mutant allele.
Swango et al. (1998) found that 18 of 19 randomly selected individuals with partial biotinidase deficiency (10 to 30% activity) were heterozygous for the D444H mutation. Previous studies had indicated that the D444H mutation results in 48% of normal enzyme activity for that allele and occurs with an estimated frequency of 0.039 in the general population. Swango et al. (1998) compared the D444H mutation to the Duarte variant of galactosemia (230400.0005). The D444H mutation in 1 allele in combination with a mutation for profound deficiency in the other allele is a common cause of partial biotinidase deficiency.
Norrgard et al. (1999) found the double mutation (A171T/D444H) to be the second most common allele identified by newborn screening, appearing in 17.3% of alleles. They observed a second double mutation (F403V/D444H); see 609019.0009. It was unknown whether A171T or F403V must act in concert with D444H to produce profound biotinyl-hydrolase and -transferase deficiencies. Either the A171T or the F403V mutation alone could produce a nonfunctional enzyme, although neither had been observed alone. Although A171T/D444H was very frequent in newborn screening alleles, it was found in none of the patients whose disorder had been detected on the basis of symptoms.
In a preconception carrier screen for 448 severe recessive childhood diseases involving 437 target genes, Bell et al. (2011) found that the D444H mutation in BTD is a polymorphism carried by asymptomatic individuals.
In an asymptomatic woman with biotinidase deficiency (253260) who was diagnosed after her child was identified by newborn screening, Wolf et al. (1997) identified a homozygous 755A-G transition, resulting in an asp252-to-gly (D252G) substitution. Her parents were heterozygous for the mutation. Her husband was heterozygous for a missense mutation (Q456H; 609019.0007). The enzyme-deficient daughter was a compound heterozygote for the mutations found in the mother and father. The son, who was identified through newborn screening, was presumably also a compound heterozygote for these 2 mutations.
Wolf et al. (1997) identified a heterozygous 1368A-C transversion in the BTD gene, resulting in a gln456-to-his (Q456H) substitution (originally published as GLN556HIS) in a man whose child was diagnosed with biotinidase deficiency (253260). The affected child was compound heterozygous for the Q456H mutation and D252G (609019.0006).
Pomponio et al. (2000) identified homozygosity for the Q456H mutation in a clinically ascertained child in the Turkish population. They also identified the Q456H mutation in homozygosity or compound heterozygosity in 2 Turkish children ascertained by newborn screening.
In a Japanese child with biotinidase deficiency (253260) identified in a pilot newborn screening program in Sapporo, Japan, Pomponio et al. (1998) identified a 1466A-C transversion in exon 4 of the BTD gene, resulting in an asn489-to-thr (N489T) substitution in the putative glycosylation site of the BTD protein. The child was treated with oral biotin supplementation from age 2 months to 5 years. Biotin supplementation was then discontinued and the child, who was 8 years old at the time of report, had remained asymptomatic. Hearing and vision testing had been normal. He showed 10.8% of mean normal serum biotinyl-hydrolase activity and trace biotinyl-transferase activity.
For discussion of the F403V/D444H double mutation in the BTD gene that was identified in patients with BTD deficiency (253260) by Norrgard et al. (1999), see 609019.0005.
In Turkish children with biotinidase deficiency (253260) identified both clinically and by newborn screening, Pomponio et al. (2000) identified a 235C-T transition in the BTD gene, resulting in an arg79-to-cys (R79C) substitution. Some patients were homozygous and some compound heterozygous.
In Turkish children with biotinidase deficiency (253260), Pomponio et al. (2000) identified homozygous 1595C-T transition in the BTD gene, resulting in a thr532-to-met (T532M) substitution in homozygous or compound heterozygous state.
Of 14 Brazilian children with biotinidase deficiency (253260) identified by newborn screening, Carvalho et al. (2019) identified 2 with a homozygous c.1081T-G transversion in exon 4 of the BTD gene, resulting in a phe361-to-val (F361V) substitution. Biotinidase enzyme activity in serum from both patients was in the partially deficient range. Serum enzyme testing in a mother from one of these patients showed biotinidase activity in the heterozygote range. Two other children were compound heterozygous for the F361V mutation and another BTD mutation, in one case with D444H (609019.0005). Biotinidase enzyme activity in serum from both children was in the partially deficient range.
Of 14 Brazilian children with biotinidase deficiency (253260) identified by newborn screening, Carvalho et al. (2019) identified one with a homozygous c.1601C-T transition in exon 4 of the BTD gene, resulting in an ala534-to-val (A534V) substitution. Biotinidase deficiency in this child was in the profoundly deficient range. Two other children were compound heterozygous for A534V and D444H (609019.0005). Biotinidase enzyme activity in serum from these children was in the partially deficient range. Based on these findings, Carvalho et al. (2019) concluded that the A534V mutation results in severe enzyme deficiency.
Bell, C. J., Dinwiddie, D. L., Miller, N. A., Hateley, S. L., Ganusova, E. E., Mudge, J., Langley, R. J., Zhang, L., Lee, C. C., Schilkey, F. D., Sheth, V., Woodward, J. E., Peckham, H. E., Schroth, G. P., Kim, R. W., Kingsmore, S. F. Carrier testing for severe childhood recessive diseases by next-generation sequencing. Sci. Transl. Med. 3: 65ra4, 2011. Note: Electronic Article. [PubMed: 21228398] [Full Text: https://doi.org/10.1126/scitranslmed.3001756]
Carvalho, N. O., del Castillo, D. M., Januario, J. N., Starling, A. L. P., Arantes, R. R., Norton, R. C., Viana, M. B. Novel mutations causing biotinidase deficiency in individuals identified by the newborn screening program in Minas Gerais, Brazil. Am. J. Med. Genet. 179A: 978-982, 2019. [PubMed: 30912303] [Full Text: https://doi.org/10.1002/ajmg.a.61137]
Cole, H., Reynolds, T. R., Lockyer, J. M., Buck, G. A., Denson, T., Spence, J. E., Hymes, J., Wolf, B. Human serum biotinidase: cDNA cloning, sequence, and characterization. J. Biol. Chem. 269: 6566-6570, 1994. [PubMed: 7509806]
Cole, H., Weremowicz, S., Morton, C. C., Wolf, B. Localization of serum biotinidase (BTD) to human chromosome 3 in band p25. Genomics 22: 662-663, 1994. [PubMed: 8001986] [Full Text: https://doi.org/10.1006/geno.1994.1449]
Gordon, A. Biotinidase mutational 'hotspot'. (Letter) Nature Genet. 13: 144-145, 1996. [PubMed: 8640218] [Full Text: https://doi.org/10.1038/ng0696-144b]
Hernandez-Vazquez, A., Wolf, B., Pindolia, K., Ortega-Cuellar, D., Hernandez-Gonzalez, R., Heredia-Antunez, A., Ibarra-Gonzalez, I., Velazquez-Arellano, A. 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. Molec. Genet. Metab. 110: 248-254, 2013. [PubMed: 24075304] [Full Text: https://doi.org/10.1016/j.ymgme.2013.08.018]
Knight, H. C., Reynolds, T. R., Meyers, G. A., Pomponio, R. J., Buck, G. A., Wolf, B. Structure of the human biotinidase gene. Mammalian Genome 9: 327-330, 1998. [PubMed: 9530634] [Full Text: https://doi.org/10.1007/s003359900760]
Norrgard, K. J., Pomponio, R. J., Hymes, J., Wolf, B. Mutations causing profound biotinidase deficiency in children ascertained by newborn screening in the United States occur at different frequencies than in symptomatic children. Pediat. Res. 46: 20-27, 1999. [PubMed: 10400129] [Full Text: https://doi.org/10.1203/00006450-199907000-00004]
Norrgard, K. J., Swango, K. L., Wolf, B. Mutation (D444H) in the biotinidase gene causes approximately 50% loss of enzyme activity and is common in the general population. (Abstract) Am. J. Hum. Genet. 59 (suppl.): A275 only, 1996.
Pomponio, R. J., Coskun, T., Demirkol, M., Tokatli, A., Ozalp, I., Huner, G., Baykal, T., Wolf, B. Novel mutations cause biotinidase deficiency in Turkish children. J. Inherit. Metab. Dis. 23: 120-128, 2000. [PubMed: 10801053] [Full Text: https://doi.org/10.1023/a:1005609614443]
Pomponio, R. J., Hymes, J., Reynolds, T. R., Meyers, G. A., Fleischhauer, K., Buck, G. A., Wolf, B. Mutations in the human biotinidase gene that cause profound biotinidase deficiency in symptomatic children: molecular, biochemical, and clinical analysis. Pediat. Res. 42: 840-848, 1997. [PubMed: 9396567] [Full Text: https://doi.org/10.1203/00006450-199712000-00020]
Pomponio, R. J., Narasimhan, V., Reynolds, T. R., Buck, G. A., Povirk, L. F., Wolf, B. Deletion/insertion mutation that causes biotinidase deficiency may result from the formation of a quasipalindromic structure. Hum. Molec. Genet. 5: 1657-1661, 1996. [PubMed: 8894703] [Full Text: https://doi.org/10.1093/hmg/5.10.1657]
Pomponio, R. J., Norrgard, K. J., Hymes, J., Reynolds, T. R., Buck, G. A., Baumgartner, R., Suormala, T., Wolf, B. Arg538 to cys mutation in a CpG dinucleotide of the human biotinidase gene is the second most common cause of profound biotinidase deficiency in symptomatic children. Hum. Genet. 99: 506-512, 1997. [PubMed: 9099842] [Full Text: https://doi.org/10.1007/s004390050397]
Pomponio, R. J., Reynolds, T. R., Cole, H., Buck, G. A., Wolf, B. Mutational hotspot in the human biotinidase gene causes profound biotinidase deficiency. Nature Genet. 11: 96-98, 1995. [PubMed: 7550325] [Full Text: https://doi.org/10.1038/ng0995-96]
Pomponio, R. J., Reynolds, T. R., Mandel, H., Admoni, O., Melone, P. D., Buck, G. A., Wolf, B. Profound biotinidase deficiency caused by a point mutation that creates a downstream cryptic 3-prime splice acceptor site within an exon of the human biotinidase gene. Hum. Molec. Genet. 6: 739-745, 1997. [PubMed: 9158148] [Full Text: https://doi.org/10.1093/hmg/6.5.739]
Pomponio, R. J., Yamaguchi, A., Arashima, S., Hymes, J., Wolf, B. Mutation in a putative glycosylation site (N489T) of biotinidase in the only known Japanese child with biotinidase deficiency. Molec. Genet. Metab. 64: 152-154, 1998. [PubMed: 9705240] [Full Text: https://doi.org/10.1006/mgme.1998.2706]
Swango, K. L., Demirkol, M., Huner, G., Pronicka, E., Sykut-Cegielska, J., Schulze, A., Wolf, B. Partial biotinidase deficiency is usually due to the D444H mutation in the biotinidase gene. Hum. Genet. 102: 571-575, 1998. Note: Erratum: Hum. Genet. 102: 712 only, 1998. [PubMed: 9654207] [Full Text: https://doi.org/10.1007/s004390050742]
Wolf, B., Norrgard, K., Pomponio, R. J., Mock, D. M., McVoy, J. R. S., Fleischhauer, K., Shapiro, S., Blitzer, M. G., Hymes, J. Profound biotinidase deficiency in two asymptomatic adults. Am. J. Med. Genet. 73: 5-9, 1997. [PubMed: 9375914] [Full Text: https://doi.org/10.1002/(sici)1096-8628(19971128)73:1<5::aid-ajmg2>3.0.co;2-u]