Institutionen för odontologi / Department of Odontology
Abstract
Linkage analysis is one of the first and essential steps in the
localization of human disease genes. In this study, the method was first
applied in mapping of the disease in two families with isolated
hyperparathyroidism (FIHP) to the hyperparathyroidism-jaw tumor (HPT-JT)
syndrome locus at 1q21-q32. The results suggest that a sunset of FlHP
families are a variant of HPT-JT. Loss of heterozygosity at 1q21-q32 was
found in tumors from a FIHP and a HPT-JT family, implying that the gene
involved is a tumor suppressor gene (Paper I).
Genetic analyses were applied to the studies of syndromic and
non-syndromic cleft lip and palate. Van der Woude syndrome (VWS), the
most common form of syndromic cleft, has been mapped to 1q32-q41. Two
Swedish and three Finnish families were mapped to 1q32-q41 and the
critical region was tentatively refined to 130-kb by observing
recombination and shared haplotypes in the families. Microdeletion of the
VWS region was unlikely. Two Finnish families were unlinked to the VWS
region in 1q thus providing the first evidence of genetic heterogeneity
in VWS. All families were tested for the possible modifying effect on the
cleft palate phenotype from a locus in 17p11.2-p11.1. Linkage was clearly
excluded, meaning that the 17p locus is not a major modifying gene
(Papers II, III).
A Swedish boy and his mother who both have cleft lip and palate were
examined for additional clinical featured. The presence of lip pits and a
distinct toe malformation led to the diagnosis of popliteal pterygium
syndrome (PPS). Our analysis showed that microdeletion of the 1q VWS
region was unlikely but linkage to the region could not be excluded
(Paper IV).
Non-syndromic cleft lip with or without cleft palate (CLP) has been
tentatively mapped to candidate loci in chromosome 4, chromosomes 2, 6
and 19 with heterogeneity. Linkage to these regions as well as the 1q VWS
locus was tested in 19 Swedish multi-generation CLP families. Our results
showed that the group of families was unlinked to any of these regions
and heterogeneity was not evidenced. This might imply a new locus or loci
in the Swedish CLP families, although linkage to individual loci could be
hidden by insignificant heterogeneity in the family group. Results from
the non-parametric linkage analysis were insignificant. Although linkage
could not be confirmed with the limited sizes of these families, data
from individual families will form the basis for future studies of
candidate genes derived from these loci (Paper V).
In summary, genetic linkage analyses have been applied to elucidate the
genetic basis of syndromic and non-syndromic cleft lip and palate,
generating important clinical and genetic data. These results will be
incorporated into the ongoing gene mapping efforts of these diseases.
Identification of the genes involved in cleft lip and palate is essential
for the diagnosis, prediction and in the future treatment of these
congenital malformations