Refinement of the Locus for Autosomal Dominant Hereditary Gingival Fibromatosis (GINGF) to a 3.8-cM Region on 2p21

Hereditary gingival fibromatosis (HGF, MIM 135300; approved gene symbol GINGF) is an oral disease characterized by enlargement of gingiva. Recently, a locus for autosomal dominant HGF has been mapped to an 11-cM region on chromosome 2p21. In the current investigation, we genotyped four Chinese HGF families using polymorphic microsatellite markers on 2p21. The HOMOG test provided evidence for genetic homogeneity, with evidence for linkage in four families (heterogeneity versus homogeneity test HOMOG, χ² = 0.00). A cumulative maximum two-point lod score of 5.04 was produced with marker D2S390 at a recombination frequency of θ = 0 in the four linked families. Haplotype analysis localized the hereditary gingival fibromatosis locus within the region defined by D2S352 and D2S2163. This region overlaps by 3.8 cM with the previously reported HGF region. Single-strand conformation polymorphism and sequence analysis of the coding region of cytochrome P450 1B1 (CYP1B1) excluded it as a likely candidate gene.     

A novel locus for maternally inherited human gingival fibromatosis at chromosome 11p15

Human isolated gingival fibromatosis is an oral disorder characterized by a slowly progressive benign enlargement of gingival tissues. The most common genetic form, hereditary gingival fibromatosis (HGF), is usually transmitted as an autosomal dominant trait. We report here for the first time a newly identified maternally inherited gingival fibromatosis in two unrelated Chinese families and mapped this disease locus to human chromosome 11p15 with a maximum two point LOD score of 8.70 at D11S4046 (θ = 0) for family 1 and of 6.02 at D11S1318 for family 2. Haplotype analysis placed the critical region in the interval defined by D11S1984 and D11S1338. A cluster of maternally expressed genes is within this critical region. We screened individuals in these two families for mutations for all known maternally expressed genes within this region. None was found either within the coding sequence or at the intron–exon boundary of these genes. Neither did we detect any loss of imprinting in three informative imprinted genes including H19, KCNQ1 downstream neighbor (KCNQ1DN) and cyclin-dependent kinase inhibitor 1C (CDKN1C). However, gene expression profile analysis revealed reduced expression of hemoglobin beta (HBB), hemoglobin delta (HBD), hemoglobin gamma A (HBG1) and hemoglobin gamma G (HBG2) genes at disease locus in HGF patients. This study suggests that genome imprinting might affect the development of HGF. Electronic supplementary material Supplementary material is available in the online version of this article at and is accessible for authorized users. Conflict Of Interest Statement: No competing financial interests.     

Genetic linkage of hereditary gingival fibromatosis to chromosome 2p21.

Gingival fibromatosis is characterized by a slowly progressive benign enlargement of the oral gingival tissues. The condition results in the teeth being partially or totally engulfed by keratinized gingiva, causing aesthetic and functional problems. Both genetic and pharmacologically induced forms of gingival fibromatosis are known. The most common genetic form, hereditary gingival fibromatosis (HGF), is usually transmitted as an autosomal dominant trait, although sporadic cases are common and autosomal recessive inheritance has been reported. The genetic basis of gingival fibromatosis is unknown. We identified an extended family (n=32) segregating an autosomal dominant form of isolated gingival fibromatosis. Using a genomewide search strategy, we identified genetic linkage (Zmax=5.05, straight theta=.00) for the HGF phenotype to polymorphic markers in the genetic region of chromosome 2p21 bounded by the loci D2S1788 and D2S441. This is the first report of linkage for isolated HGF, and the findings have implications for identification of the underlying genetic basis of gingival fibromatosis.     

A mutation in the SOS1 gene causes hereditary gingival fibromatosis type 1

Hereditary gingival fibromatosis (HGF) is a rare, autosomal dominant form of gingival overgrowth. Affected individuals have a benign, slowly progressive, nonhemorrhagic, fibrous enlargement of the oral masticatory mucosa. Genetic loci for autosomal dominant forms of HGF have been localized to chromosome 2p21-p22 (HGF1) and chromosome 5q13-q22 (HGF2). To identify the gene responsible for HGF1, we extended genetic linkage studies to refine the chromosome 2p21-p22 candidate interval to approximately 2.3 Mb. Development of an integrated physical and genetic map of the interval identified 16 genes. Sequencing of these genes, in affected and unaffected HGF1 family members, identified a mutation in the Son of sevenless-1 (SOS1) gene in affected individuals. In this report, we describe the genomic structure of the SOS1 gene and present evidence that insertion of a cytosine between nucleotides 126,142 and 126,143 in codon 1083 of the SOS1 gene is responsible for HGF1. This insertion mutation, which segregates in a dominant manner over four generations, introduces a frameshift and creates a premature stop codon, abolishing four functionally important proline-rich SH3 binding domains normally present in the carboxyl-terminal region of the SOS1 protein. The resultant protein chimera contains the wild-type SOS1 protein for the N-terminal amino acids 1-1083 fused to a novel 22-amino acid carboxyl terminus. Similar SOS1 deletion constructs are functional in animal models, and a transgenic mouse construct with a comparable SOS1 chimera produces a phenotype with skin hypertrophy. Clarification of the functional role of this SOS1 mutant has implications for understanding other forms of gingival fibromatosis and corrective gingival-tissue management.     

A gene for Usher syndrome type I (USH1A) maps to chromosome 14q.

Usher syndrome (US) is an autosomal recessive disease characterized by congenital hearing impairment and retinitis pigmentosa. It is the most frequent cause of deaf-blindness in adults and accounts for 3 to 6% of deaf children. Here, we report the genetic mapping of a gene for US type I (USH1A), the most severe form of the disease, to the long arm of chromosome 14, by linkage to probe MLJ14 at the D14S13 locus in 10 families of Western France ancestry (Z = 4.13 at theta = 0). Among them, 8 families originated from a small area of the Poitou-Charentes region (Z = 3.78 at theta = 0), suggesting that a founder effect could be involved. However, since not all US type I families were found to be linked to this locus, the present study provides evidence for genetic heterogeneity of this condition (heterogeneity versus homogeneity test HOMOG, P < 0.05; heterogeneity versus no linkage, P < 0.01).     

The gene for juvenile hyaline fibromatosis maps to chromosome 4q21

Juvenile hyaline fibromatosis (JHF) is an autosomal recessive condition characterized by multiple subcutaneous nodular tumors, gingival fibromatosis, flexion contractures of the joints, and an accumulation of hyaline in the dermis. We performed a genomewide linkage search in two families with JHF from the same region of the Indian state of Gujarat and identified a region of homozygosity on chromosome 4q21. Dense microsatellite analyses within this interval in five families with JHF who were from diverse origins demonstrate that all are compatible with linkage to chromosome 4q21 (multipoint LOD score 5.5). Meiotic recombinants place the gene for JHF within a 7-cM interval bounded by D4S2393 and D4S395.     

Linkage of Wolfram syndrome to chromosome 4p16.1 and evidence for heterogeneity.

Wolfram syndrome (DIDMOAD syndrome; MIM 222300) is an autosomal recessive neurodegenerative disorder characterized by juvenile-onset diabetes mellitus and bilateral optic atrophy. Previous linkage analysis of multiply affected families indicated that the gene for Wolfram syndrome is on chromosome 4p, and it produced no evidence for locus heterogeneity. We have investigated 12 U.K. families with Wolfram syndrome, and we report confirmation of linkage to chromosome 4p, with a maximum two-point LOD score of 4.6 with DRD5, assuming homogeneity, and of 5.1, assuming heterogeneity. Overlapping multipoint analysis using six markers at a time produced definite evidence for locus heterogeneity: the maximum multipoint LOD score under homogeneity was <2, whereas when heterogeneity was allowed for an admixture a LOD of 6.2 was obtained in the interval between D4S432 and D4S431, with the peak close to the marker D4S3023. One family with an atypical phenotype was definitely unlinked to the region. Haplotype inspection of the remaining 11 families, which appear linked to chromosome 4p and had typical phenotypes, revealed crossover events during meiosis, which also placed the gene in the interval D4S432 and D4S431. In these families no recombinants were detected with the marker D4S3023, which maps within the same interval.     

Additional glomangioma families link to chromosome 1p: no evidence for genetic heterogeneity

Venous malformations are a common abnormality of the vasculature that may occur sporadically or, more rarely, as an autosomal dominant trait. One familial form of venous malformations has previously been linked to chromosome 9p. Mutations in the gene encoding Tie2, an endothelial specific receptor tyrosine kinase, have been identified in four different families. Glomangiomas are a subtype of venous malformations with glomus cell involvement. These cutaneous lesions can be inherited as an autosomal dominant disease with reduced penetrance and variable expressivity. We present evidence of linkage to chromosome 1p21-1p22 using four new glomangioma families, with a combined maximum two-point lod score of 7.32 at marker D1S2804. Markers D1S2129 and D1S2881 define the 24-cM linkage interval determined by recombination within affected individuals. A recent report also showed linkage of the glomangioma locus to chromosome 1p. A total of 9 families now map to this region, suggesting a decreased likelihood of locus heterogenity in familial glomangiomas. Investigation of candidate genes within the interval should provide new insights into lesion formation in inherited venous malformations.     

Further evidence for a locus for cutaneous malignant melanoma-dysplastic nevus (CMM/DN) on chromosome 1p, and evidence for genetic heterogeneity.

Assignment of a susceptibility locus for cutaneous malignant melanoma-dysplastic nevus (CMM/DN) to chromosome 1p remains controversial. We examined the relationship between CMM/DN and markers D1S47, PND, and D1S160 on seven new families (set B) plus updated versions of six previously reported families (set A). Three linkage analyses were performed: (1) CMM alone--all individuals without confirmed melanoma or borderline lesions were considered unaffected (model I); (2) CMM/DN with variable age at onset and sporadics (model II); and (3) CMM/DN using the model of Bale et al. (model III). For CMM alone and D1S47, Zmax = 3.12 at theta = .10. For D1S160 and CMM alone, Zmax = 1.76 at theta = .10. PND showed no evidence for linkage to CMM alone. Models II and III showed strong evidence for linkage to D1S47, D1S160, and PND in the set A pedigrees but not in the set B families. We tested for homogeneity of CMM/DN (model II) by splitting families into two groups on the basis of (1) the proportion of CMM/DN cases and (2) the occurrence of immune-related tumors. In group 1 there was significant evidence of heterogeneity with both D1S47 and D1S160, and in group 2 there was significant evidence of heterogeneity with D1S160. Thus, diagnostic, clinical, and genetic heterogeneity are the likely reasons that previous studies have failed to confirm linkage of CMM/DN to chromosome 1p. The results showed significant evidence for a CMM locus linked to D1S47, as well as significant evidence for heterogeneity with only a subset of the families appearing linked to chromosome 1p.     

A new locus for hereditary gingival fibromatosis (GINGF2) maps to 5q13-q22

Gingival fibromatosis (GINGF) is an oral disorder characterized by enlargement of the gingiva. It occurs either as the sole phenotype or combined with other symptoms. Thus far, one GINGF locus has been mapped on chromosome 2, at 2p21, and a second possible locus has been mapped to 2p13. However, the genes responsible for this disorder have not been elucidated. We identified a four-generation Chinese GINGF family in which the disease manifests within 1 year after birth. After exclusion of the two known GINGF loci in this family, we performed a genome-wide search to map the chromosome location of the responsible gene. We identified a new locus, GINGF2, on chromosome 5q13-q22 with a maximum two-point lod score of 4.31 at D5S1721 (theta = 0.00). Haplotype analysis placed the critical region in the interval defined by D5S1491 and D5S1453. Within this region, calcium/calmodulin-dependent protein kinase IV (CAMK4) is a strong candidate.     

Linkage analysis of maturity-onset diabetes of the young (MODY): Genetic heterogeneity and nonpenetrance

We have analyzed the inheritance of maturity-onset diabetes of the young (MODY) on chromosome 20 in a large multigeneration family, the R.-W. family, and in two other MODY families. Of the four branches of the R.-W. pedigree which have been studied, two have documented early onset of non-insulin-dependent diabetes mellitus (NIDDM), while there is no evidence of early onset in the other two branches. The early-onset branches have apparently inherited the same D20S16 allele from the affected parent, while another D20S16 allele was inherited in the two branches without evidence of early onset. A test for homogeneity, the M-test, using the results of two-point linkage analysis with D20S16 indicates heterogeneity between early- and late-onset branches of the R.-W. family (P less than or equal to .014). In addition, analysis strongly suggests that MODY as expressed in the EDI and WIS families is unlinked to loci on chromosome 20 (P less than or equal to .018-.004). Comparable results are seen when the data are analyzed by the HOMOG program. Three polymorphic loci-D20S16, D20S17, and ADA--show no recombination with the MODY locus when two-point linkage analysis is used in the early-onset branches of the family. The multipoint lod score in the early-onset branches of the R.-W. family is 10.16, with the most likely location being between D20S4 and D20S17. Multipoint linkage analysis using the CHROMPICS option of the program CRI-MAP has been used to follow inheritance of the MODY disease locus. This analysis has identified two cases of possible nonpenetrance in the early-onset branches of the family (odds of at least 156:1), as determined by the appearance of apparent isolated double crossovers at the MODY locus in these unaffected individuals.     

Genetic heterogeneity of Usher syndrome: analysis of 151 families with Usher type I

Usher syndrome type I is an autosomal recessive disorder marked by hearing loss, vestibular areflexia, and retinitis pigmentosa. Six Usher I genetic subtypes at loci USH1A-USH1F have been reported. The MYO7A gene is responsible for USH1B, the most common subtype. In our analysis, 151 families with Usher I were screened by linkage and mutation analysis. MYO7A mutations were identified in 64 families with Usher I. Of the remaining 87 families, who were negative for MYO7A mutations, 54 were informative for linkage analysis and were screened with the remaining USH1 loci markers. Results of linkage and heterogeneity analyses showed no evidence of Usher types Ia or Ie. However, one maximum LOD score was observed lying within the USH1D region. Two lesser peak LOD scores were observed outside and between the putative regions for USH1D and USH1F, on chromosome 10. A HOMOG chi(2)((1)) plot shows evidence of heterogeneity across the USH1D, USH1F, and intervening regions. These results provide conclusive evidence that the second-most-common subtype of Usher I is due to genes on chromosome 10, and they confirm the existence of one Usher I gene in the previously defined USH1D region, as well as providing evidence for a second, and possibly a third, gene in the 10p/q region.     

Linkage of cutaneous malignant melanoma/dysplastic nevi to chromosome 9p, and evidence for genetic heterogeneity.

We examined the relationship between cutaneous malignant melanoma/dysplastic nevi (CMM/DN) and chromosome 9p in 13 pedigrees with two or more living cases of invasive melanoma. We used two highly informative (CA)n repeats, D9S126 and IFNA, previously implicated in familial malignant melanoma (MLM), to conduct linkage analysis. Three analyses were performed: (1) CMM alone--all individuals without either confirmed melanoma or borderline lesions were considered unaffected (model A); (2) CMM/DN with both variable age at onset and sporadics (model B); and (3) CMM affecteds only--all individuals either without confirmed melanoma or with borderline lesions were designated "unknown" (model C). There was significant evidence for linkage to IFNA in all three models. For CMM alone, the maximum lod score (Zmax) was 4.36 at theta = .10 for model A and 3.39 at theta = .10 for model C. For CMM/DN (model B), Zmax = 3.05 at theta = .20. There was no significant evidence for linkage between CMM alone or CMM/DN and chromosome 9p marker D9S126. In addition, there was significant evidence for heterogeneity when a homogeneity test allowing for linkage to chromosome 9p or chromosome 1p or neither region was used. These results suggest that there is an MLM susceptibility locus on chromosome 9p but that familial melanoma is heterogeneous and not all families with CMM/DN are linked to a locus in this region.     

Linkage of Familial Schizophrenia to Chromosome 13q32

Over the past 4 years, a number of investigators have reported findings suggestive of linkage to schizophrenia, with markers on chromosomes 13q32 and 8p21, with one recent study by Blouin et al. reporting significant linkage to these regions. As part of an ongoing genome scan, we evaluated microsatellite markers spanning chromosomes 8 and 13, for linkage to schizophrenia, in 21 extended Canadian families. Families were analyzed under autosomal dominant and recessive models, with broad and narrow definitions of schizophrenia. All models produced positive LOD scores with markers on 13q, with higher scores under the recessive models. The maximum three-point LOD scores were obtained under the recessive-broad model: 3.92 at recombination fraction (theta).1 with D13S793, under homogeneity, and 4.42 with alpha=.65 and straight theta=0 with D13S793, under heterogeneity. Positive LOD scores were also obtained, under all models, for markers on 8p. Although a maximum two-point LOD score of 3.49 was obtained under the dominant-narrow model with D8S136 at straight theta=0.1, multipoint analysis with closely flanking markers reduced the maximum LOD score in this region to 2. 13. These results provide independent significant evidence of linkage of a schizophrenia-susceptibility locus to markers on 13q32 and support the presence of a second susceptibility locus on 8p21.     

A variant of Freeman-Sheldon syndrome maps to 11p15.5-pter.

Distal arthrogryposis type 1 (DA1) and Freeman-Sheldon syndrome (FSS) are the two most common known causes of inherited multiple congenital contractures. We recently have characterized a new disorder (DA2B) with a phenotype intermediate between DA1 and FSS. We report the mapping of a gene that causes DA2B to chromosome 11p15.5-pter. Linkage analysis in a single kindred generated a positive LOD score of 5.31 at theta = 0 with the marker D11S922, and recombinants localize the gene to an approximately 3.5-6.5-cM region between the marker TH and the telomere. Analysis of additional families improves the LOD score to 6.45 at theta = 0 and suggests linkage homogeneity for DA2B.     

Mapping of the regulatory subunits RI beta and RII beta of cAMP-dependent protein kinase genes on human chromosome 7.

The genes encoding the regulatory subunits RI beta (locus PRKAR1B) and RII beta (locus PRKAR2B) of human cAMP-dependent protein kinase have been mapped in the basic CEPH (Centre d'Etude du Polymorphisme Humain) family panel of 40 families to chromosome 7p and 7q, respectively, using the enzymes HindIII and BanII recognizing the corresponding restriction fragment length polymorphisms (RFLPs). Previous data from the CEPH database and our present RFLP data were used to construct a six-point local framework map including PRKAR1B and a seven-point framework map including PRKAR2B. The analysis placed PRKAR1B as the most distal of the hitherto mapped 7p marker loci and resulted in an unequivocal order of pter-PRKAR1B-D7S21-D7S108-D7S17-D7S149- D7S62-cen, with a significantly higher rate of male than female recombination between PRKAR1B and D7S21. The 7q regulatory gene locus, PRKAR2B, could also be placed in an unambigous order with regard to the existing CEPH database 7q marker loci, the resulting order being cen-D7S371-(COL1A2,D7S79)-PRKAR2B-MET-D7S87++ +-TCRB-qter. Furthermore, in situ hybridization to metaphase chromosomes physically mapped PRKAR2B to band q22 on chromosome 7.     

Pseudoxanthoma elasticum maps to an 820-kb region of the p13.1 region of chromosome 16

We have performed linkage analysis on 21 families with pseudoxanthoma elasticum (PXE) using 10 polymorphic markers located on chromosome 16p13.1. The gene responsible for the PXE phenotype was localized to an 8-cM region of 16p13.1 between markers D16S500 and D16S3041 with a maximum lod score of 8.1 at a recombination fraction of 0.04 for marker D16S3017. The lack of any locus heterogeneity suggests that the major predisposing allele for the PXE phenotype is located in this region. Haplotype studies of a total of 36 PXE families identified several recombinations that further confined the PXE gene to a region (< 1 cM) between markers D16S3060 and D16S79. This PXE locus was identified within a single YAC clone and several overlapping BAC recombinants. From sequence analysis of these BAC recombinants, it is clear that the distance between markers D16S3060 and D16S79 is about 820 kb and contains a total of nine genes including three pseudogenes. We predict that mutations in one of the expressed genes in the locus will be responsible for the PXE phenotype in these families.     

Genetic analysis of 24 French families with multiple endocrine neoplasia type 2A.

The gene for multiple endocrine neoplasia type 2A (MEN2A) has been mapped to the pericentromeric region of chromosome 10 by linkage analysis. Thirty-four families with multiple cases of medullary carcinoma of the thyroid (MTC), including 24 families with origins in France, have been typed with nine polymorphic markers spanning the centromere of chromosome 10. No recombination was observed between the MEN2A locus and either of the four loci D10Z1 (lod score 12.79), D10S102 (lod score 6.38), D10S94 (lod score 7.76), and D10S34 (lod score 5.94). There was no evidence for genetic linkage heterogeneity in the panel of 34 families. Haplotypes were constructed for a total of 11 polymorphisms in the MEN2A region, for mutation-bearing chromosomes in 24 French families and for 100 spouse controls. One haplotype was present in four MEN2A families but was not observed in any control (P less than .01). Two additional families share a core segment of this haplotype near the MEN2A gene. It is likely that these six families have a common affected ancestor. Because the incidence of pheochromocytoma among carriers varies from 0% to 74% within these six families, it is probable that additional factors modify the expression of the MEN2A gene.     

Localization of two genes for Usher syndrome type I to chromosome 11.

The Usher syndromes (USH) are autosomal recessive diseases characterized by congenital sensorineural hearing loss and progressive pigmentary retinopathy. While relatively rare in the general population, collectively they account for approximately 6% of the congenitally deaf population. Usher syndrome type II (USH2) has been mapped to chromosome 1q (W. J. Kimberling, M. D. Weston, C. M?ller, et al., 1990, Genomics 7: 245-249; R. A. Lewis, B. Otterud, D. Stauffer, et al., 1990, Genomics 7: 250-256), and one form of Usher syndrome type I (USH1) has been mapped to chromosome 14q (J. Kaplan, S. Gerber, D. Bonneau, J. Rozet, M. Briord, J. Dufier, A. Munnich, and J. Frezal, 1990. Cytogenet. Cell Genet. 58: 1988). These loci have been excluded as regions of USH genes in our data set, which is composed of 8 French-Acadian USH1 families and 11 British USH1 families. Both of these sets of families show linkage to loci on chromosome 11. Linkage analysis demonstrates locus heterogeneity between these sets of families, with the French-Acadian families showing linkage to D11S419 (Z = 4.20, theta = 0) and the British families showing linkage to D11S527 (Z = 6.03, theta = 0). Genetic heterogeneity of the data set was confirmed using HOMOG and the M test (log likelihood ratio > 10(5)). These results confirm the presence of two distinct USH1 loci on chromosome 11.     

Possible genetic heterogeneity in the Saethre-Chotzen syndrome

Saethre-Chotzen syndrome is an autosomal dominant acrocephalosyndactyly syndrome whose gene has been assigned to chromosome 7p. Cytogenetic and linkage analyses have enabled the interval encompassing the disease gene to be delimited to a short region of chromosome 7p15.3–p21.2. Based on the genetic analysis of three unreported families, we confirm the location of the disease gene(s) in the interval defined by loci D7S664 and D7S493 (Z_max = 4.78 at * = 0 at the D7S488 locus) but fail to decide whether one or more disease-causing genes map in this genetic interval. Received: 2 January 1996 / Revised: 21 March 1996