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© 1997 Oxford University Press 166-171

Footnote

BTKbase, mutation database for X-linked agammaglobulinemia (XLA)

BTKbase, mutation database for X-linked agammaglobulinemia (XLA) Mauno Vihinen* , Bernd H. Belohradsky 1 , Robert N. Haire 2 , Elke Holinski-Feder 3 , Sau-Ping Kwan 4 , Ilkka Lappalainen , Heikki Lehväslaiho 5 , Tracy Lester 6 , Alfons Meindl 3 , Hans D. Ochs 7 , Juha Ollila , Igor Vorechovsky 8 , Michael Weiss 1 and C. I. Edvard Smith 8,9

Department of Biosciences, Division of Biochemistry, University of Helsinki, PO Box 56, Helsinki , FIN-00014, Finland , 1 Abteilung für Infektionsimmunologie, Dr von Haunersches Kinderspital, Klinikum Innenstadt der Universität München, Lindwurmstrasse 4, D-80337 München , Germany , 2 USF College of Medicine, Department of Pediatrics, All Children's Hospital, 801 Sixth Street South, St Petersburg , FL 33701-4899, USA , 3 Abteilung für Pädiatrische Genetik, Kinderpoliklinik, Klinikum Innenstadt der Universität München, Goethestrasse 29, D-80336 München , Germany , 4 Department of Immunology, Rush Medical School, Chicago , IL 60612, USA , 5 CSC Scientific Computing, PO Box 405, Tietotie 6, 02101 Espoo , Finland , 6 Unit of Clinical Genetics, Institute of Child Health, 30 Guilford Street, London WC1N 1EH, UK , 7 Department of Pediatrics, University of Washington, Seattle , WA 98195, USA , 8 Center for BioTechnology, Department of Biosciences at Novum, Karolinska Institute, S-14157 Huddinge , Sweden and 9 Department of Immunology, Microbiology, Pathology and Infectious Diseases (IMPI), Karolinska Institute, Huddinge University Hospital, S-14186 Huddinge , Sweden

Received October 2, 1996; Accepted October 8, 1996

ABSTRACT

X-linked agammaglobulinemia (XLA) is an immunodeficiency caused by mutations in the gene coding for Bruton's agammaglobulinemia tyrosine kinase (BTK). A database (BTKbase) of BTK mutations has been compiled and the recent update lists 368 entries from 318 unrelated families showing 228 unique molecular events. In addition to mutations the database lists also some polymorphisms and site-directed mutations. Each patient is given a unique patient identity number (PIN). Information is provided regarding the phenotype including symptoms. Mutations in all the five domains of BTK have been noticed to cause the disease, the most common event being missense mutations. The mutations appear almost uniformly throughout the molecule and frequently affect CpG sites forming arginine residues. These hot spots have generally pyrimidines 5 ' and purines 3 ' to the mutated cytosine. A decreased frequency of missense mutations was found in the TH, SH3 and the upper lobe of the kinase domain. The putative structural implications of all the missense mutations are given in the database showing 228 unique molecular events, including a novel missense mutation causing an R28C substitution as previously seen in the Xid mouse.

INTRODUCTION

X-linked agammaglobulinemia (XLA) is a hereditary immunodeficiency caused by mutations in the gene coding for Bruton's agammaglobulinemia tyrosine kinase (BTK) ( 1 , 2 ). Patients with XLA have a decreased number of mature B cells in their peripheral blood and show a lack of all immunoglobulin isotypes causing susceptibility to severe bacterial infections ( 3 ). The BTK gene is mapped to the midportion of the long arm of X-chromosome at Xq21.3-Xq22 ( 4 - 7 ). The 37.5 kb gene contains 19 exons, 18 of which code for a 77 kDa protein ( 8 - 11 ). BTK is expressed in all hematopoietic lineages except for T lymphocytes and plasma cells ( 12 ). The murine gene for Btk has also been cloned and sequenced ( 10 ).

BTK is crucial for signaling in B cells ( 13 , 14 ). It belongs to a group of related cytoplasmic protein tyrosine kinases (PTKs) formed by TEC ( 15 ) ITK/TSK/EMT ( 16 , 17 ) and BMX ( 18 ), known as the Tec family. The Tec family proteins consist of five distinct structural domains ( 1 , 2 , 19 , 20 ), which are from the N-terminus, pleckstrin homology (PH) domain of ~120 amino acids, Tec homology (TH) domain (~60-80 residues), Src homology 3 (SH3) domain of ~60 residues, SH2 domain (~100 amino acids) and the catalytic kinase domain of ~280 residues. The BTK protein is 659 residues long. Mutations in all the five domains have been noticed to cause XLA ( 21 - 23 ). The structural consequences of the mutations in all the domains except for TH have been studied based on computer-aided molecular modeling ( 21 - 29 ).

PH domains have been suggested to be involved in membrane ( 30 ), heterotrimeric G protein ( 31 , 32 ) and protein kinase C ( 33 ) binding. It has been suggested based on the mutational and structural information that the domain has a 2-fold function ( 14 , 27 ). The N-terminal portion seems to be involved in membrane binding whereas the C-terminal [alpha]-helix and its extension in the adjacent TH domain are responsible for G [beta][gamma] binding. The three dimensional structures of pleckstrin and spectrin PH domain in complex with phosphoinositides ( 30 , 34 ) have indicated the residues that are responsible for binding. Protein kinase C has been proposed to bind to the N-terminal half of the BTK PH domain ( 33 ). The first PH domain mutation was found in the Xid (X-linked immunodeficiency) mouse ( 35 , 36 ).

The TH domain has two distinct features ( 19 , 20 ). The N-terminal Btk motif of 27 residues seems to be an extension of the PH domain. About 30 residues following the PH domain have been shown to be important for [beta][gamma] binding ( 31 ). The whole TH domain is typical only for the Tec family ( 20 ), but the region corresponding to the Btk motif is important also for other [beta][gamma] binding PH domains ( 31 , 37 ). Although the PH domain extensions generally do not share significant sequence similarity, they have a stretch of basic residues in common ( 31 ). This region is crucial for G [beta][gamma] binding in [beta]ARK ( 38 ) having effect on affinity ( 37 ). The C-terminal region of the TH domain contains one or two proline rich regions (PRRs) which have been shown to interact with the SH3 domains of Src family PTKs FYN, LYN and HCK ( 39 ). In TEC the corresponding region is recognized by the LYN SH3 domain ( 40 ). The PRRs form presumably polyproline type II helices which are known to interact with SH3 domains.

The SH2 and SH3 domains each recognize short peptide motifs bearing either phosphotyrosine (pTyr) residue or polyprolines, respectively. These compact functional modules appear widely in signalling molecules, but SH2 domains are explicitly involved only in PTK signalling pathways ( 41 ). These domains link BTK to partner molecules. Amino acids surrounding the pTyr can increase the affinity by three orders of magnitude. SH3 domains bind peptides and proteins that have a left-handed polyproline type II helix. Since these helices are almost symmetrical, the direction of binding depends on the residues surrounding the prolines ( 41 ).

The kinase domain is the only catalytic region in the Tec family kinases. A conserved ATP binding site locates between two structural lobes. The upper lobe, which is formed mainly of [beta]-strands, has turned relative to the lower [alpha]-helical lobe in the inactive form of the enzyme. All the known kinases contain several highly conserved residues, which are involved in substrate and cofactor binding as well as in some structurally crucial sites.

BTKbase

To coordinate BTK mutation analysis an international study group was established in 1994 ( 21 ). BTK mutation data, both published and directly submitted information, has been collected into a database called BTKbase ( 21 - 23 , 42 - 44 ). The database contains information about the mutations and XLA patients. The study group gives for each patient an individual patient identity number (PIN). The PIN consists of the type of mutation and a running number indicating mutations affecting the same amino acid or the same non-coding region. The PIN is given as soon as a mutation is available to the study group. Scientists are encouraged to contact the study group before publishing their mutation data to get the PINs. Data can be kept confidential until published. A more detailed description of the formation of PINs and an example of a coded entry is given in Vihinen et al. ( 45 ).

The database contains the following information for each patient (when available). The first lines are used to provide the necessary data for the identification of the entry and plain English descriptions of the mutation. These are followed by reference lines and lines which characterise formally the mutation. Last are the lines describing various parameters from the patient. Other immunodeficiency mutation databases ( 46 - 49 ) follow the same guidelines, which facilitates development of common tools, e.g. for submission and analysis of data.

Table 1 XLA-causing mutations in the BTK coding exons
Exon

Amino acids

Missense

Nonsense

Deletion

Insertion

2

1-47

10/23/29

3/9/9

2/2/2

1/1/1

3

48-80

2/2/3

1/1/1

7/9/9

3/7/7

4

81-103

1/1/1

1/1/1

1/1/1

5

104-130

2/2/2

1/1/1

3/3/3

6

131-173

2/2/2

6/6/7

5/5/7

1/1/1

7

174-196

1/1/1

1/1/1

3/4/4

2/4/4

8

197-259

1/1/1

3/9/11

7/7/8

1/1/1

9

260-280

1/1/1

1/1/1

1/1/1

10

281-298

2/7/9

2/3/4

11

299-325

2/5/5

1/1/1

4/5/6

12

326-367

6/6/9

2/3/3

1/1/1

13

368-392

1/1/1

2/4/4

1/1/1

1/1/1

14

393-450

5/6/7

3/4/5

1/1/1

15

451-522

10/25/25

6/13/14

3/3/3

1/1/3

16

523-544

5/8/15

1/2/2

6/9/9

17

545-583

6/11/11

2/2/2

2/2/2

1/1/1

18

584-636

13/16/24

5/5/7

3/3/3

3/3/3

19

637-659

5/7/7

1/1/1

1/1/1

Total

73/123/151

41/66/74

50/57/61

18/24/26

For the larger insertions and deletions the starting exon is used for classification. The numbers separated by slashes are for different mutations, affected families and affected individuals.

MAJOR FINDINGS FROM THE ANALYSIS OF THE BTKbase

There are altogether 368 patients in the database with XLA mutations that are scattered along the BTK gene (Fig. 1 ). The patients represent 318 unrelated families. The proportion of unique mutations is 72% (228 cases), which is reduced compared with the previous report. The distribution of the mutations in the five structural domains is approximately according to the length of the domains (Fig. 1 ). Exonic mutations are distributed as follows: 123 families have missense mutations, 66 nonsense mutations, 24 insertions and 57 deletions (Table 1 ). In addition there are 49 intron mutations affecting splice sites. Three double mutations and a single triple mutatation have been detected. Mutations confined to the promoter region have not been found. The gene defect of nine gross deletions have not been characterized in detail. The figures are calculated from the total number of identified mutations i.e. all the alterations in the families having multiple mutations are taken into account.


Figure 1 . Distribution of the mutations in the BTK protein (mutation spectrum). ( a ) Domain organization. The number of different types of mutations in the BTK; (b) mutations not causing frame shift i.e. missense and inframe insertions and deletions (the four inframe mutations are indicated below the X-axis), ( c ) all the frameshift mutations (nonsense, insertions and deletions), ( d ) nonsense mutations, ( e ) frameshift deletions and ( f ) frameshift insertions. In (c) and (f) four mutations at residue 70 are presented. These mutations in unrelated families occur in a stretch of seven A nucleotides, and exact localization of a single A insertion is unknown.

The distribution of the types of the mutations in the exons is shown in Table 1 . No missense mutations have been detected in exons 8 and 9 from residue 205 to 287, which could indicate higher tolerance for mutations in the TH and SH3 domains or redundant functions. As expected, the missense mutations appear mainly in the first two positions within the codon. Of the 123 different missense mutations 43 appear at position 1 and 72 at position 2, but only eight at position 3. Eighty-nine (72%) were transitions and 33 (28%) transversions. The most common alterations were G to A ( 37 ) and C to T ( 19 ). These figures are comparable with those obtained with the smaller registry ( 22 ).

The nonsense mutations were mainly transitions ( 46 ) whereas there were 20 transversions. Forty-one of the nonsense mutations appear at position 1, only five and 20 at positions 2 and 3, respectively. The most common change was C to T at position 1 altering CGA to TGA (21 occurrences). Half of the nonsense mutations were alterations to TGA. Substitutions in eight patients alter the start codon and prevent expression of the protein. Altogether, there were in the missense and nonsense mutations 135 transitions and 54 transversions corresponding to 71 and 29% of the single amino acid substitutions, which is in agreement with previous results ( 22 , 50 ). There are somewhat more nonsense mutations in the exons 2 and 15.

The most frequently affected sites are CpG dinucleotides, which are known to be mutational hotspots ( 51 ). 5-methylcytosine bases have been demonstrated at the hotspot sites ( 52 ). The G+C content in the exons of the coding region is 47%. The 33 CpG dinucleotides in the coding region form only 3.3% of the gene. However, CG to TG or CA mutations constitute 29% of the single base substitutions. Mutations in CpG sites cause highly significant overexpression ( P < 0.001) of missense mutations in the exons 2, 10 and 15 and of nonsense mutations in the exons 2 and 15. The most mutated CpG sites have generally pyrimidines 5' and purines 3' to the mutated 5-methylcytosine ( 53 ). Eight of 18 CpG containing arginine residues were affected, whereas none of the residual 15 CpG sites encoding non-arginine residues was mutated. Six of 18 arginine residues do not appear to be conserved and no mutations affected these residues. Mutations are likely to be found also in the remaining four conserved sites (R123, 133, 332 and 615). CpG dinucleotides are involved in all the cases where at least five families have the same mutation except for the initiation site (M1X).

Intron mutations in 43 families cause aberrant splicing. These mutations are concentrated mainly at locations +1 (10 occurrences) and -2 ( 11 ). Skipping of the exon 9 causes an inframe deletion in the C-terminus of the SH3 domain ( 24 ). Introns 5 and 10 are also frequently mutated. The low frequency of mutations in the conserved intron positions +2 (six cases) and -1 ( 3 ) is concordant with other human diseases ( 54 ).

Insertions and deletions have been characterized from 24 and 56 families, respectively. Fourteen of the insertions and 23 of the deletions are of one base. The longest insertion is of 26 bases, whereas the largest characterized deletion is of 503 bp. The larger deletions encompass whole exons. Direct repeats appear in the immediate vicinity of all these mutations as noticed also in other genes ( 55 ). There are, in addition to the splice site mutation resulting in the inframe skipping of exon 9, eight inframe deletions. All these mutations delete substantial parts of the protein. Deletion of G302 presumably disturbs the conserved [beta]-strand scaffolding in the SH2 domain. Inframe insertion of seven amino acids at position 103 has been suggested to destroy one of the [beta]-strands and thus affect the integrity of the PH domain ( 27 ). Another inframe insertion of two residues at 605 could impair [alpha]-helix G in the kinase domain. There is very significant overexpression ( P < 0.001) of insertions in the exons 3 and 7 and of deletions in the exons 3 and 16.

The immunoglobulin levels and B cell numbers are very low or not detectable in most patients, although some have higher levels. The severity of XLA can vary even among family members carrying the same mutation (reviewed in 3 ). Due to the screening technique most of the data in the BTKbase is for severe (classical) XLA patients. There are only 20 cases (6.3%) with mild XLA phenotype. In many instances (eight cases) the same mutation causes also classical XLA even in the same family. A more detailed discussion of the mild diseases is given in ( 22 ).

Many of the mutations affect functionally significant, conserved residues. The distribution in the secondary structural elements were calculated based on sequence alignments and modeled structures of the domains. Most of the missense mutations appear in the coil structures (52 families), while there are 40 in [alpha]-helices and 27 in [beta]-strands. Four sites in the TH domain could not be defined due to lack of structural information. The low number of mutations in the [beta]-strands is especially pronounced in the kinase domain where the upper lobe consists of [beta]-strands but it has only 15% of the missense and nonsense mutations in the kinase domain although it constitutes ~36% of its length.


Figure 2 . Stereo pair of the kinase domain. The polypeptides are shown as ribbons running along the backbone. ATP and Mg 2+ ions are shown in green. On the structure to the left, the residues conserved in protein tyrosine kinases (56) are colored in cyan and those mutated in mild disease having patients are in yellow to the right. Note that mutations shown to the right can cause also classical XLA. The modeling of the region has been previously described (25).

The missense mutations in the PH domain are in the putative binding region except for one presumably structural alteration caused by an insertion. Of particular interest is the arginine residue 28 containing a CpG site affected in the Xid mouse. In humans seven unrelated families have so far been shown to carry mutations causing R28H. Recently, a human missense mutation identical to the one in the Xid mouse was reported to BTKbase. Thus, in this mutation a C to T change causes an R28C substititon. There are four missense mutations in the TH domain but none in the SH3 domain. Based on computer modeling and molecular dynamics simulations the truncated SH3 domain (skipping exon 9) has stable albeit not functional conformation ( 24 ). This mutation has been noticed in three patients from two families. Most of the amino acid substitutions in the SH2 domain impair pTyr binding. In the kinase domain, the mutations are on one side of the molecule with the exception of six mutations (Fig. 2 a and b). This face of the enzyme is in charge of the ATP, Mg 2+ and substrate binding. Although a large number of these mutations affect the cofactor or putative substrate binding residues, many alterations appear in structurally crucial sites. Some of the mutations causing less severe XLA are not in the immediate vicinity of the binding sites or structurally crucial positions.

DISTRIBUTION OF THE DATABASE

The continuously updated database is freely available via anonymous ftp at csb.ki.se in the directory pub/btkbase. Use anonymous as username and your e-mail address as password. World Wide Web distribution is available at BTKbase . Inquiries and new mutation data can be sent to mauno.vihinen{at}helsinki.fi, preferably by using the submission form at the Web pages.

ACKNOWLEDGEMENTS

This work was supported by Biocentrum Helsinki, the Swedish Medical Research Council, the Swedish Cancer Society, the Åke Wiberg Foundation, and European BIOMED concerted action `PL1321'.

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