Search

Hereditary hemorrhagic telangiectasia (HHT) or Osler-Rendu-Weber (ORW) disease is an autosomal dominant vascular dysplasia. Initial linkage studies identified an ORW gene localized to 9q33-q34 but with some families clearly excluding this region. A probable correlation in clinical phenotype between the 9q3-linked families and unlinked families was described with a significantly lower incidence of pulmonary arteriovenous malformations observed in the unlinked families. In this study we examined four unrelated ORW families for which linkage to chromosome 9q33-q34 has been previously excluded. Linkage was established for all four families to markers on chromosome 12, with a combined maximum lod score of 10.77 (theta = 0.04) with D12S339. Mapping of crossovers using haplotype analysis indicated that the candidate region lies in an 11-CM interval between D12S345 and D12S339, in the pericentromeric region of chromosome 12. A map location for a second ORW locus is thus established that exhibits a significantly reduced incidence of pulmonary involvement.

Approximately 10% of newborns with congenital hypothyroidism are unable to convert iodide into organic iodine. This iodide organification defect has a prevalence of 1 in 40,000 newborns and may be caused by defects in the thyroid peroxidase enzyme (TPO), the hydrogen peroxide-generating system, the TPO substrate thyroglobulin, or inhibitors of TPO. We identified a high incidence of severe hypothyroidism due to a complete iodide organification defect in the youngest generation of five nuclear families belonging to an inbred Amish kindred. Genealogical records permitted us to trace their origin to an ancestral couple 7-8 generations back and to identify an autosomal recessive pattern of inheritance. Initial studies of homozygosity by descent using two polymorphic markers within the TPO gene showed no linkage to the phenotype. In fact, 4 of 15 affected siblings from 2 of the nuclear families were heterozygous, resulting in homozygosity values of 73% and 53% in affected and unaffected family members, respectively. A genome-wide homozygosity screen using DNA pools from affected and unaffected family members localized the defect to a locus close to the TPO gene. Linkage analysis using 4 additional polymorphic markers within the TPO gene reduced the number of homozygous unaffected siblings to zero without altering the percent homozygosity initially found in the affected. Sequencing of the TPO gene revealed 2 missense mutations, E799K and R648Q. TPO 779K was found in both alleles of the 11 affected homozygotes, both mutations were present in each of the 3 affected compound heterozygotes, and there were no TPO mutations in 1 subject with hypothyroidism of different etiology. These results demonstrate the power of the DNA pooling strategy in the localization of a defective gene and the pitfalls of linkage analysis when 2 relatively rare mutations coexist in an inbred population.

Limb-girdle muscular dystrophies (LGMDs) are a group of neuromuscular diseases presenting great clinical heterogeneity. Mutations in CANP3, the gene encoding muscle-specific calpain, were used to identify this gene as the genetic site responsible for autosomal recessive LGMD type 2A (LGMD2A; MIM 253600). Analyses of the segregation of markers flanking the LGMD2A locus and a search for CANP3 mutations were performed for 21 LGMD2 pedigrees from various origins. In addition to the 16 mutations described previously, we report 19 novel mutations. These data indicate that muscular dystrophy caused by mutations in CANP3 are found in patients from all countries examined so far and further support the wide heterogeneity of molecular defects in this rare disease.

The syndrome of hereditary hyperparathyroidism and jaw tumors (HPT-JT) is characterized by inheritance, in an autosomal dominant pattern, of recurrent parathyroid adenomas, fibro-osseous tumors of the mandible and/or maxilla, Wilms tumor, and parathyroid carcinoma. This syndrome is clinically and genetically distinct from other endocrine neoplasia syndromes and appears to result from mutation of an endocrine tumor gene designated "HRPT2." We studied five HPT-JT families (59 persons, 20 affected); using PCR-based markers, we instituted a genomewide linkage search after excluding several candidate genes. Lod scores were calculated at various recombination fractions (theta), penetrance 90%. We mapped HRPT2 to the long arm of chromosome 1 (1q21-q31). The maximal lod score was 6.10 at theta = .0 with marker D1S212, or10(6) odds in favor of linkage. In six hereditary Wilms tumor families (96 persons, 29 affected), we found no linkage to 1q markers closely linked with HRPT2 (lod scores -15.6 [D1S191] and -17.8 [D1S196], theta = .001). Nine parathyroid adenomas and one Wilms tumor from nine members of three HPT-JT families were examined for loss of heterozygosity at linked loci. The parathyroid adenomas and Wilms tumor showed no loss of heterozygosity for these DNA markers. Our data establish that HRPT2, an endocrine tumor gene on the long arm of chromosome 1, is responsible for the HPT-JT syndrome but not for the classical hereditary Wilms tumor syndrome.

The multiple endocrine neoplasia type 1 (MEN1) locus has been previously localized to 11q13 by combined tumour deletion mapping and linkage studies. Family linkage analysis has defined the locus order as 11 cen-PGA-(PYGM, MEN1)-(D11S97, D11S146)-INT2-11qter, and tumour deletion mapping studies have suggested that the MEN1 locus is proximal to D11S146 but distal to PYGM. In order to establish further the location of MEN1, we have utilized the seven polymorphic DNA probes: D11S288, D11S149, PGA, PYGM, D11S97, D11S146 and INT2, in linkage studies of 339 members (116 affected) from 27 MEN1 families. Linkage between MEN1 and 6 of the 7 loci was established, and the highest peak lod scores [Z(theta)] were observed with PYGM and D11S97 at Z(theta) = 13.71, theta = 0.047 and Z(theta) = 13.76, theta = 0.076 respectively. Multilocus analysis suggested the most likely locus order as: 11 pter-(D11S288, D11S149)-11 cen-PGA-PYGM-MEN1-D11S97-D11S146-INT2-1 1qter. In addition, an examination of individual recombinants indicated a centromeric location of D11S149 in relation to D11S288. Thus, the results of our study, which favoured a location of MEN1 proximal to D11S97 and distal to PYGM, have established a panel of recombinants that will facilitate further meiotic mapping studies of the MEN1 locus.

Multiple endocrine neoplasia type 2B (MEN 2B) is similar to MEN 2A in that both autosomal dominant syndromes include medullary thyroid cancers and pheochromocytomas. It is distinct in that MEN 2B patients have much earlier age of onset with more aggressive tumors and mucosal neuromas of the lips and tongue. The neuromas allow ascertainment generally before age 5. Studies of two and three generations of 14 MEN 2B families disclosed close linkage of the MEN 2B gene to DNA markers to which MEN2A had been linked. Multipoint analysis utilizing additional results in three generations of a 15th family have disclosed a peak total lod score of 8.89 at the midpoint between the centromere markers D10Z1 and RBP3 on the long arm (band q11). One recombinant was observed between D10Z1 and MEN2B, but this individual was not recombinant with D10S94. These studies suggest physical proximity of MEN2A and MEN2B but do not establish allelism for the gene(s).

We have identified three different tyrosinase gene mutant alleles in four unrelated patients with type IB ("yellow") oculocutaneous albinism (OCA) and thus have demonstrated that type IB OCA is allelic to type IA (tyrosinase negative) OCA. In an inbred Amish kindred, type IB OCA results from homozygosity for a Pro----Leu substitution at codon 406. In the second family, type IB OCA results from compound heterozygosity for a type IA OCA allele (codon 81 Pro----Leu) and a novel type IB allele (codon 275 Val----Phe). In the third patient, type IB OCA results from compound heterozygosity for the same type IB allele (codon 275 Val----Phe) and a novel type IB OCA allele. In a fourth patient, type IB OCA results from compound heterozygosity for the codon 81 type IA OCA allele and a type IB allele that contains no identifiable abnormalities; dysfunction of this type IB allele apparently results from a mutation either well within one of the large introns or at some distance from the tyrosinase gene. In vitro expression of the Amish type IB allele in nonpigmented HeLa cells demonstrates that the Pro----Leu substitution at codon 406 greatly reduces but does not abolish tyrosinase enzymatic activity, a finding consistent with the clinical phenotype.

A large previously reported family with hyperparathyroidism has been reinvestigated recently because of the occurrence of multiple ossifying jaw fibromas in two affected members of the third generation similar to the jaw tumors of four of five affected members of the first generation. These maxillary and mandibular tumors can be differentiated from the "brown tumors" of hyperparathyroidism because they can appear and enlarge even though the hypercalcemia is surgically corrected. These tumors are histologically distinct fibroosseous lesions without the giant cells seen in "brown tumors." The parathyroid enlargement was mostly uniglandular, with multiple tumors found occasionally. Studies in DNA linkage were performed within this large family and a similar family in Houston to determine if the gene for this syndrome, termed HRPT2, is linked to DNA markers on chromosome 11, to which the gene for multiple endocrine neoplasia (MEN) type 1 has been linked. (This linkage is supported by our findings in one family with MEN 1 reported here.) Linkage studies were also performed with markers on chromosome 10, to which the genes for MEN 2A and MEN 2B have been linked. Evidence against close linkage with chromosome 10 and chromosome 11 markers suggests that this clinically distinct syndrome is also genetically distinct.

Adrenocortical adenomas causing hyperaldosteronism in two women heterozygous at the X chromosome-linked glucose-6-phosphate dehydrogenase (G-6-PD) locus exhibited only one G-6-PD isoenzyme. This finding suggests a clonal development for these benign tumors and contrasts with the multicellular origin of parathyroid adenomas reported in three patients from our institution in 1977 and found subsequently in seven other hyperparathyroid women whose cases are reported here. One of these seven patients had hereditary hyperparathyroidism. In this case each of three glands removed showed both A and B G-6-PD isoenzymes in similar ratios as were found in normal tissues. The multicellular origin of hereditary hyperparathyroidism is compatible with the concept of parathyroid lesions being manifestations of the first genetic event in Knudson's two-mutational-event theory for the initiation of cancer. The multicellular origin of sporadic parathyroid tumors suggest that they are caused by some factors stimulating many cells in the parathyroid glands. The young average age of onset of eight cases of parathyroid cancer from five families with hereditary hyperparathyroidism in the literature is also compatible with Knudson's theory. G-6-PD studies of other aldosteronomas, parathyroid tumors, and other endocrine neoplasms may provide important information about the pathogenesis of these conditions.

The Republic of San Marino (RSM) is a 23-square mile independent country within Italy with a population of 20,000. A large percentage of deaths have been found to be due to gastic cancer (9.2% of all death certificate diagnoses for 1969 through 1973). The frequency of gastric cancer in the families of all 36 patients (78% male) who were born and died in RSM with this diagnosis for this period was compared with the frequency in relatives of age and sex-matched controls. Although 42--44% of both groups had relatives with death certificate diagnoses of stomach cancer, 25% of the patients had first degree relatives affected versus 5.6% of the controls. A high prevalence has also been reported in the area of Italy near RSM. San Marino's size and stability of population provide unique opportunities for elucidating genetic and environmental etiological factors in stomach cancer.

Improved approaches to the problem of heterozygote detection for phenylketonuria (PKU) were developed in this study. The discrimination was based on 85 obligate heterozygotes and 45 controls who were neither pregnant nor on birth control medication. The best separation between hetrozygotes and normals was achieved with a linear discriminant function involving the logarithms of the serum concentrations of phenylalanine, tyrosine, and tryptophan. The theoretical overlap area between the distributions of heterozygotes and controls based on the above function, was 3.75%. In the 19 obligate hetrozygotes and 13 controls who were either pregnant or on birth control medication, the best separation was achieved with a linear discriminant function involving the logarithms of the serum concentrations of phenylalanine and tyrosine. The theoretical overlap area was 8.23%. The genetic accuracy of the discriminant function was confirmed by testing the results with parental-child exclusions, segregation analysis, and the frequency of heterozygosity in nonrelated collateral spouses. Finally, there was evidence suggesting that the antihypertensive agent, aldomet, alters serum tyrosine and tryptophan levels.

Hairy cutaneous malformations of the palms and soles were observed in four generations of a French-Canadian family. The lesions were asymptomatic, bilaterally symmetrical, and involved small areas of skin of the central proximal part of the palms near the wrist and the medial aspect of the longitudinal arch of the foot. The appearance suggested a difference in quality of the skin rather than simply the presence of hair follicles. Examination of a biopsy specimen showed skin containing hair follicles. The pattern of inheritance was autosomal dominant with definate male-to-male transmission. Genetic linkage studies were generally noninformative, but evidence was obtained against close chromosomal linkage of this trait to the histocompatibility antigen (HL-A) or Rh blood group locus. The only other known case of a familiar condition was reported by Schnitzler in 1973.