Albright hereditary osteodystrophy and del(2)(q37.3) in four unrelated individuals

Phelan, Mary C.; Rogers, R. Curtis; Clarkson, Katie; Bowyer, Frank P.; Levine, Michael A.; Estabrooks, Laurel L.; Severson, M. C.; Dobyns, William B.

doi:10.1002/ajmg.1320580102

Cited by 102 publications

(85 citation statements)

References 31 publications

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“…2q37 deletion syndrome is a chromosomal disorder characterized by developmental delay, dysmorphic facies, skeletal abnormalities, and an increased risk of congenital heart defects (17)(18)(19)(20). Although most cases have no associated malignancies, three children with constitutional 2q37 monosomy and Wilms' tumor have been reported (21)(22)(23)(24).…”

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confidence: 99%

Loss of Heterozygosity at 2q37 in Sporadic Wilms' Tumor: Putative Role for miR-562

Drake

Ruteshouser

Natrajan

et al. 2009

Clinical Cancer Research

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Purpose Wilms tumor is a childhood cancer of the kidney with an incidence of ~1 in 10,000. Co-occurrence of Wilms tumor with 2q37 deletion syndrome, an uncommon constitutional chromosome abnormality, has previously been reported in three children. Given these are independently rare clinical entities, we hypothesized that 2q37 harbors a tumor suppressor gene important in Wilms tumor pathogenesis. Experimental Design To test this, we performed loss of heterozygosity (LOH) analysis in a panel of 226 sporadic Wilms tumor samples and mutation analysis of candidate genes. Results LOH was present in at least 4% of cases. Two tumors harbored homozygous deletions at 2q37.1, supporting the presence of a tumor suppressor gene that follows a classical two-hit model. However, no other evidence of second mutations was found, suggesting that heterozygous deletion alone may be sufficient to promote tumorigenesis in concert with other genomic abnormalities. We show that miR-562, a microRNA within the candidate region, is expressed only in kidney and colon and regulates EYA1, a critical gene for renal development. miR-562 expression is reduced in Wilms tumor and may contribute to tumorigenesis by deregulating EYA1. Two other candidate regions were localized at 2q37.3 and 2qter but available data from patients with constitutional deletions suggest these probably do not confer a high risk for Wilms tumor. Conclusions Our data support the presence of a tumor suppressor gene at 2q37.1 and suggest that in individuals with constitutional 2q37 deletions, any increased risk for developing Wilms tumor likely correlates with deletions encompassing 2q37.1.

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confidence: 99%

Loss of Heterozygosity at 2q37 in Sporadic Wilms' Tumor: Putative Role for miR-562

Drake

Ruteshouser

Natrajan

et al. 2009

Clinical Cancer Research

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“…The paternal-specific imprinting pattern shown for an alternative GNAS1 promoter on both alleles in PHP-Ib patients probably leads to decreased G s␣ expression in renal proximal tubules (25). Finally, other loci have been associated with AHO-like syndromes (26,27).…”

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Molecular Analysis of the GNAS1 Gene for the Correct Diagnosis of Albright Hereditary Osteodystrophy and Pseudohypoparathyroidism

et al. 2003

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Pseudohypoparathyroidism (PHP) is a heterogeneous disease characterized by PTH resistance and classified as types Ia, Ib, Ic, and II, according to its different pathogenesis and phenotype. PHP-Ia patients show G s␣ protein deficiency, PTH resistance, and typical Albright hereditary osteodystrophy (AHO). Heterozygous mutations in the GNAS1 gene encoding the G s␣ protein have been identified both in PHP-Ia and in pseudopseudohypoparathyroidism (PPHP), a disorder with isolated AHO. A single GNAS1 mutation may be responsible for both PHP-Ia and PPHP in the same family when inherited from the maternal and the paternal allele, respectively, suggesting that GNAS1 is an imprinted gene. To evaluate whether molecular diagnosis is a useful tool to characterize AHO and PHP when testing for G s␣ activity and PTH resistance is not available, we have performed GNAS1 mutational analysis in 43 patients with PTH resistance and/or AHO. Sequencing of the whole coding region of the GNAS1 gene identified 11 mutations in 18 PHP patients, eight of which have not been reported previously. Inheritance was ascertained in 13 cases, all of whom had PHP-Ia: the mutated alleles were inherited from the mothers, who had AHO (PPHP), consistent with the proposed imprinting mechanism. GNAS1 molecular analysis confirmed the diagnosis of PHP-Ia and PPHP in the mutated patients. Our results stress the usefulness of this approach to obtain a complete diagnosis, expand the GNAS1 mutation spectrum, and illustrate the wide mutation heterogeneity of PHP and PHP-Ia. PHP (OMIM 103580) was the first human disease to be ascribed to deficient responsiveness to a hormone by otherwise normal target organs (1). It consists of a heterogeneous group of endocrine disorders, whose common feature is resistance to PTH, as shown by hypocalcemia, hyperphosphatemia, and elevation of serum PTH despite normal renal function (2). PTH stimulates the formation of intracellular cAMP by adenylyl cyclase through the activation of G s protein (3, 4). G s protein belongs to the superfamily of heterotrimeric G proteins formed of three subunits (␣, ␤, ␥) encoded by separate genes (5). They mediate signal transduction across cell membranes by coupling extracellular receptors to intracellular effector proteins. The activity of hormone-sensitive adenylate cyclase is regulated by at least two G proteins, one stimulatory (G s ) and one inhibitory (G i ). G protein specificity is defined by its specific ␣-subunit. G s␣ , which binds GTP and stimulates adenylyl cyclase, has GTPase activity and couples multiple receptors to the stimulation of adenylyl cyclase, including those for PTH, TSH, and LH/FSH.

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“…AHO-like syndrome has been mainly associated with isolated, primarily terminal 2q37 deletions. In addition to the pure deletions, monosomy of 2q37 has also been described due to unbalanced de novo (11)(12)(13)(14) or familial translocations (15,16), though the described partner chromosomes have not included chromosome 21.…”

Section: Discussionmentioning

confidence: 99%

Two cases of deletion 2q37 associated with segregation of an unbalanced translocation 2;21: choanal atresia leading to misdiagnosis of CHARGE syndrome

Fernández-Rebollo¹,

Pérez²,

Martínez-Bouzas³

et al. 2009

European Journal of Endocrinology

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Context: The phenotypic variability of patients with syndromes presenting with dysmorphism makes clinical diagnosis difficult, leading to an exhaustive genetic study to determine the underlying mechanism so that a proper diagnosis could be established. Objective: To genetically characterize siblings, the older sister diagnosed with Albright hereditary osteodystrophy and the younger one with CHARGE syndrome. Design: Clinical case report. Methods: Clinical, biochemical, and radiological studies were performed on the family. In addition, molecular genetic studies including sequencing of GNAS, typing of microsatellites on 2q and 21q, and multiplex ligation-dependent probe amplification of subtelomeric regions were performed, as well as confirmatory fluorescent in situ hybridization analysis. Results: The genetic analysis revealed that both sisters presented a 2q37 deletion due to the maternal unbalanced segregation of a 2;21 translocation. Conclusions: This is the first report of a 2q37 deletion where differential diagnosis of CHARGE syndrome is needed due to the appearance of choanal atresia.

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Albright hereditary osteodystrophy and del(2)(q37.3) in four unrelated individuals

Cited by 102 publications

References 31 publications

Loss of Heterozygosity at 2q37 in Sporadic Wilms' Tumor: Putative Role for miR-562

Loss of Heterozygosity at 2q37 in Sporadic Wilms' Tumor: Putative Role for miR-562

Molecular Analysis of the GNAS1 Gene for the Correct Diagnosis of Albright Hereditary Osteodystrophy and Pseudohypoparathyroidism

Two cases of deletion 2q37 associated with segregation of an unbalanced translocation 2;21: choanal atresia leading to misdiagnosis of CHARGE syndrome

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