Rubinstein-Taybi Syndrome: spectrum of CREBBP mutations in Italian patients.
BACKGROUND
Rubinstein-Taybi Syndrome (RSTS, MIM 180849) is a rare congenital disorder characterized by mental and growth retardation, broad and duplicated distal phalanges of thumbs and halluces, facial dysmorphisms and increased risk of tumors. RSTS is caused by chromosomal rearrangements and point mutations in one copy of the CREB-binding protein gene (CREBBP or CBP) in 16p13.3. To date mutations in CREBBP have been reported in 56.6% of RSTS patients and an average figure of 10% has ascribed to deletions.


METHODS
Our study is based on the mutation analysis of CREBBP in 31 Italian RSTS patients using segregation analysis of intragenic microsatellites, BAC FISH and direct sequencing of PCR and RT-PCR fragments.


RESULTS
We identified a total of five deletions, two of the entire gene and three, all in a mosaic condition, involving either the 5' or the 3' region. By direct sequencing a total of 14 de novo mutations were identified: 10 truncating (5 frameshift and 5 nonsense), one splice site, and three novel missense mutations. Two of the latter affect the HAT domain, while one maps within the conserved nuclear receptor binding of (aa 1-170) and will probably destroy a Nuclear Localization Signal. Identification of the p.Asn1978Ser in the healthy mother of a patient also carrying a de novo frameshift mutation, questions the pathogenetic significance of the missense change reported as recurrent mutation. Thirteen additional polymorphisms, three as of yet unreported, were also detected.


CONCLUSIONS
A high detection rate (61.3%) of mutations is confirmed by this Italian study which also attests one of the highest microdeletion rate (16%) documented so far.
Bentivegna
Angela
A
Division of Medical Genetics, San Paolo School of Medicine, University of Milan, Italy. angela.bentivegna@unimib.it
Milani
Donatella
D
Gervasini
Cristina
C
Castronovo
Paola
P
Mottadelli
Federica
F
Manzini
Stefano
S
Colapietro
Patrizia
P
Giordano
Lucio
L
Atzeri
Francesca
F
Divizia
Maria T
MT
Uzielli
Maria L Giovannucci
ML
Neri
Giovanni
G
Bedeschi
Maria F
MF
Faravelli
Francesca
F
Selicorni
Angelo
A
Larizza
Lidia
L
D000293:Adolescent; D000328:Adult; D000595:Amino Acid Sequence; D050882:CREB-Binding Protein / Q000737:chemistry / Q000235:genetics*; D002648:Child; D002675:Child, Preschool; D004252:DNA Mutational Analysis; D005260:Female; D006801:Humans; D007558:Italy; D008297:Male; D008969:Molecular Sequence Data; D009154:Mutation; D019913:Nuclear Localization Signals; D010375:Pedigree; D017354:Point Mutation; D012415:Rubinstein-Taybi Syndrome / Q000175:diagnosis / Q000235:genetics*; D016415:Sequence Alignment; D017384:Sequence Deletion
D019913:Nuclear Localization Signals; D050882:CREB-Binding Protein; C494363:CREBBP protein, human