Transforming growth factor-beta receptor type 1 (TGFBR1) is not associated with non-syndromic cleft lip with or without cleft palate in patients of Central European descent.
OBJECTIVE
Transforming growth factor-beta (TGF-β) type 1 receptor (also known as activin receptor-like kinase 5, ALK5) is expressed in palatal tissue during embryogenesis. Experimental studies in transgenic mice with a genetic deletion of Alk5 showed that TGF-β type 1 receptor is required for upper lip and midline fusion of the hard and soft palate. In humans, association of TGF-β type 1 receptor gene (TGFBR1) and the development of non-syndromic cleft lip with or without cleft palate (NSCL/P) had been observed in a multiethnic sample of Chinese, Philippine, Indian and Turkish families. In order to re-evaluate the relevance of these findings, we carried out a family-based association study among 218 NSCL/P families of Central European descent.


METHODS
Genomic DNA was obtained from peripheral blood of 218 complete parent-offspring triads with NSCL/P. The sample comprised 14 patients with cleft lip only (CLO) and 204 patients with cleft lip and palate (CLP). Genotyping and transmission disequilibrium test (TDT) were performed on all 218 triads with a total of 17 tagging single-nucleotide polymorphisms (SNPs). We also performed testing for extended haplotypes and a log-linear model by Weinberg was used to screen parent-of-origin effects. Furthermore the use of estimates for the relative risks (RR) of Weinberg's model was obtained.


RESULTS
TDT analysis revealed no significant transmission distortion, neither at the level of individual markers nor at the level of haplotypes. Similarly negative results were obtained when we restricted our analysis to the subgroup of patients with CLP (n=204). Relative risk calculations (RR) of the children's and mothers' genotypes obtained negative results, after correction of p-values for multiple testing. Likewise application of Weinberg's log-linear model did not find any evidence for parent-of-origin effects in our sample.


CONCLUSIONS
Despite the ample evidence supporting the role of TGF-β type 1 receptor as a critically important and widespread morphogenetic regulator of craniofacial development in murine models, our results do not support TGFBR1 as major risk factor for NSCL/P in patients of Central European descent.
Reutter
Heiko
H
Institute of Human Genetics, University of Bonn, Wilhelmstrasse 31, D-53111 Bonn, Germany. reutter@uni-bonn.de
Birnbaum
Stefanie
S
Mende
Meinhard
M
de Assis
Nilma Almeida
NA
Hoffmann
Per
P
Lacava
Amalia Diaz
AD
Herms
Stefan
S
Braumann
Bert
B
Scheer
Martin
M
Lauster
Carola
C
Schmidt
Gül
G
Schiefke
Franziska
F
Dunsche
Anton
A
Martini
Markus
M
Knapp
Michael
M
Kramer
Franz-Josef
FJ
Nöthen
Markus M
MM
Mangold
Elisabeth
E
D000015:Abnormalities, Multiple / Q000453:epidemiology / Q000601:surgery; D000818:Animals; D000831:Animals, Newborn; D002971:Cleft Lip / Q000453:epidemiology / Q000235:genetics* / Q000601:surgery; D002972:Cleft Palate / Q000453:epidemiology / Q000235:genetics* / Q000601:surgery; D015331:Cohort Studies; D004195:Disease Models, Animal; D005060:Europe / Q000453:epidemiology; D005260:Female; D018507:Gene Expression Regulation, Developmental; D020022:Genetic Predisposition to Disease / Q000453:epidemiology*; D005828:Genetics, Population; D006801:Humans; D015994:Incidence; D007231:Infant, Newborn; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010375:Pedigree; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D000077293:Receptor, Transforming Growth Factor-beta Type I; D018125:Receptors, Transforming Growth Factor beta / Q000235:genetics*; D018570:Risk Assessment; D013045:Species Specificity; D013577:Syndrome
D018125:Receptors, Transforming Growth Factor beta; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; C000625841:TGFBR1 protein, human; C000625842:Tgfbr1 protein, mouse