V. Moschese et al., X-chromosome inactivation and mutation pattern in the Bruton's tyrosine kinase gene in patients with X-linked agammaglobulinemia, MOL MED, 6(2), 2000, pp. 104-113
Citations number
41
Categorie Soggetti
Research/Laboratory Medicine & Medical Tecnology","Medical Research General Topics
Background: The diagnosis of X-linked agammaglobulinemia (XLA) is not alway
s clearcut. Not all XLA conform to the classic phenotype and less than 50%
of affected boys have a family history of immunodeficiency. Mutations in th
e gene for Brutton's tyrosine kinase (BTK) are responsible for the majority
of agammaglobulinemia cases. However, a certain proportion of patients may
have mutations involving other genes, although they show with an XLA pheno
type. We performed BTK gene mutation analysis in 37 males with presumed XLA
and analyzed the pattern of X-chromosome inactivation (XCI) in 31 mothers
to evaluate the relevance of these approaches to diagnosis and genetic coun
seling.
Materials and Methods: Twenty affected males with a sporadic occurrence and
17 familial cases belonging to nine families were enrolled within the fram
ework of the Italian Multicenter Clinical Study on XLA. We used non-isotopi
c RNase cleavage assay (NIRCA), followed by cDNA sequence determination to
screen for BTK mutations and X-chromosome inactivation analysis for carrier
detection.
Results: Using the cDNA-based approach, the identification of BTK gene abno
rmalities confirmed the clinical diagnosis of XLA in 31 of 37 affected infa
nts. Missense was the most frequent mutational event and the kinase domain
was mostly involved. In addition, nine novel mutations were identifed. In s
poradic cases, BTK gene abnormalities were identified in 9 out of 10 patien
ts whose mothers had a nonrandom pattern of XCI and in 5 out of 6 patients
whose mother had a random pattern of XCI. With the exception of one family,
all patients with a familial occurrence and born to mothers with a nonrand
om pat tern of XCI had mutations of the BTK gene.
Conclusions: Our findings indicate that in sporadic cases BTK gene sequenci
ng is the only reliable tool for a definitive diagnosis of XLA and support
XCI as the first diagnostic tool in the mothers of affected males in multip
le generations. Furthermore, our molecular analysis confirms that 10-20% of
BTK-unaltered patients have disorders caused by defects in other genes.