Genetics of Familial ParagangliomasGenetics of familial paragangliomas: Past, present, and future
Section snippets
Phenotype
Human genetics research explores how variations at the genetic level (i.e., cause) affect variations at the phenotypic level (i.e, effect) and relies heavily on the phenotype description, which is obtained by clinical and laboratory assessment. The phenotype of paraganglioma refers to the presence of tumors derived from paraganglionic tissue (i.e., the extra-adrenal chromaffin cell system).32 Paraganglioma tumors generally are classified on the basis of their anatomic location and common
Characterization of Hereditary Paraganglioma Pedigrees
The first step in the genetic analysis of paraganglioma tumors includes identification of families and characterization of genetic transmission patterns. The familial nature of paraganglioma tumors has been known for more than half a century. In 1933, Chase19 described two sisters with carotid body tumors, and Goekoop26 described familial jugular body tumors. Carotid body tumors were seen in members of three successive generations, transmitted in an autosomal-dominant pattern of inheritance.5,
Genetic Mapping of PGL Loci
Identification of genes responsible for hereditary paraganglioma began with the genetic mapping of the susceptibility genes to specific chromosomal regions. The mapping was performed by genetic linkage analysis. Linkage analysis determined which chromosomal region cosegregated with PGL in affected individuals in pedigrees using polymorphic DNA markers. This chromosomal region then was evaluated physically to identify the responsible gene. In a large Dutch pedigree with hereditary paraganglioma,
Physical Mapping of the New PGL1 Critical Region
Identification of the PGL1 gene required physical localization of candidate genes to the genetic interval defined by the genetic recombination events. First, the author's group built a complete overlapping clone set (contig) spanning the whole critical region (Baysal et al, unpublished results). This high-resolution clone contig not only helped them to fine-map neighboring genes and short segments of expressed DNA sequences that can be amplified by PCR (ESTs) but also provided them with the
Genetic Mimicry of the Response of the Carotid Body to Chronic Hypoxic Stimulation
The oxygen-sensing role of the carotid body was implicated in paraganglioma tumor development under certain conditions. Humans and other mammals, including cattle, dogs, rabbits, and guinea pigs living at high altitudes have heavier and larger carotid bodies and an increased incidence of carotid body tumors than those living at sea level.2, 3, 24, 62 Histologic analyses showed hyperplasia–anaplasia of the carotid body chemoreceptor cells, which presumably resulted from sustained stimulation by
Identification of the Role of cybS in Cellular Oxygen Sensing
The extreme phenotypic similarity between the hereditary paraganglioma tumors and the carotid body tumors arising from chronic hypoxic stimulation suggests that the cybS protein is associated closely with the hypoxic responsiveness of the paraganglionic system. It has been postulated that hypoxic stimulation activates a transcription factor, hypoxia-inducible factor 1.66 The activated hypoxia-inducible factor 1 stimulates the synthesis of erythropoietin, which increases red cell mass; vascular
Summary
Genetic studies of familial paragangliomas and the appreciation of chronic hypoxic stimulation as a potential tumorigenic factor have affected the understanding of the pathogenesis of these rare tumors. These investigative studies show that once the presence of any underlying chronic hypoxic condition is excluded, genetic defects are major causative factors in head and neck paragangliomas (Table 1). The familial basis of these tumors has been established firmly with the identification of at
References (79)
- et al.
Carotid body tumor associated with hyperparathyroidism
Ann Vasc Surg
(1994) - et al.
Chief cell hyperplasia in the human carotid body at high altitudes: Physiologic and pathologic significance
Hum Pathol
(1976) - et al.
Gene mutations in the succinate dehydrogenase subunit SDHB cause susceptibility to familial pheochromocytoma and to familial paraganglioma
Am J Hum Genet
(2001) - et al.
Genomic organization and precise physical location of protein phosphatase 2A regulatory subunit: A β-isoform gene on chromosome band 11q23
Gene
(1998) - et al.
A high-resolution STS, EST, and gene-based physical map of the hereditary paraganglioma region on chromosome 11q23
Genomics
(1997) - et al.
Multiple familial cutaneous glomangioma: A pedigree of four generations and critical analysis of histologic and genetic differences of glomus tumors
J Am Acad Dermatol
(2000) Gastric stromal sarcoma, pulmonary chondroma, and extra-adrenal paraganglioma (Carney's triad): Natural history, adrenocortical component, and possible familial occurrence
Mayo Clin Proc
(1999)- et al.
Characterization of the human SDHD gene encoding the small subunit of cytochrome b (cybS) in mitochondrial succinate-ubiquinone oxidoreductase
Biochim Biophys Acta
(1999) - et al.
A report of familial carotid body tumors and multiple extra-adrenal pheochromocytomas
J Urol
(1991) - et al.
Paragangliomas of the head and neck region: A pathologic study of tumors from 71 patients
Hum Pathol
(1979)
Role of basic FGF and oxygen in control of proliferation, survival, and neuronal differentiation in carotid body chromaffin cells
Dev Biol
Heme-based sensors in biological systems
Curr Opin Chem Biol
High-altitude hypoxia and chemodectomas
Hum Pathol
Molecular genetics of succinate-ubiquinone oxidoreductase in eukaryotes
Prog Nucleic Acid Res Mol Biol
Perspectives on oxygen sensing
Cell
The sins of the fathers and mothers: Genomic imprinting in mammalian development
Cell
Genomic imprinting in hereditary glomus tumours: Evidence for new genetic theory
Lancet
Paragangliomas of the head and neck region show complete loss of heterozygosity at 11q22–q23 in chief cells and the flow-sorted DNA aneuploid fraction
Hum Pathol
Founder effect in PGL1 in hereditary head and neck paraganlioma families from the Netherlands
Am J Hum Genet
Oxygen sensing and signaling: Impact on the regulation of physiologically important genes
Respir Physiol
Chronic hypoxia and chemodectomas in bovines at high altitudes
Arch Pathol Lab Med
Multiple glomus tumours
J Laryngol Otol
De tumoren van het glomus jugulare
Fine mapping of an imprinted gene for familial nonchromaffin paragangliomas on chromosome 11q23
Am J Hum Genet
Mutations in SDHD, a mitochondrial complex II gene, in hereditary paraganglioma
Science
Repositioning the hereditary paraganglioma critical region on chromosome band 11q23
Hum Genet
Division of type I and endothelial cells in the hypoxic rat carotid body
Acta Anat (Basel)
Familial paragangliomas: The emerging impact of molecular genetics on evaluation and management
Am J Otol
Inherited microdeletions in the Angelman's and Prader-Willi syndromes define an imprinting centre on human chromosome 15
Nat Genet
Oxygen sensing and molecular adaptation to hypoxia
Physiol Rev
Parental origin of transcription from the human GNAS1 gene
J Med Genet
Mitochondrial reactive oxygen species trigger hypoxia-induced transcription
Proc Natl Acad Sci USA
Familial and bilateral tumors of the carotid body
J Pathol Bacteriol
Hereditary tumors of the carotid bodies and chronic obstructive pulmonary disease
Cancer
Involvement of an NAD(P)H oxidase as a Po2 sensor protein in the rat carotid body
Biochem J
Imprinting in Albright's hereditary osteodystrophy
J Med Genet
Multiple paragangliomas in neurofibromatosis: A new neuroendocrine neoplasia
Neurology
The carotid body in animals at high altitude
J Pathol
Search for imprinting effects in the hereditary paraganglioma critical region on chromosome band 11q23: Allelic expression analysis of PPP2R1B, POU2AF1, D11S966E and methylation analysis of two Notl sites associated with novel genes [abstract]
Am J Hum Genet
Cited by (0)
The research in the author's laboratory is supported by a Competitive Medical Research Fund from the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania.