Hereditary Brachydactyly Associated with Hypertension

Bilginturan, N; Zileli, S; Karacadag, S; Pirnar, T

doi:10.1136/jmg.10.3.253

Cited by 83 publications

(60 citation statements)

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“…This syndrome was described in a large Turkish pedigree, and includes severe hypertension and strokes in early life as well as brachydactyly (shortened fingers) and short stature (Bilginturan et al 1973). Luft and co-workers meticulously characterized these patients.…”

Section: Autosomal Dominant Hypertension With Brachydactylymentioning

confidence: 99%

“…Under these conditions, genetic abnormalities that markedly impact blood pressure variation should also materialize as stroke genes. For monogenic forms of hypertension, several reports of increased stroke frequency exist, including hypertension with brachydacytly (Bilginturan et al 1973), glucocorticoid remediable hypertension (Rich et al 1992;Litchfield et al 1998), apparent mineralocorticoid excess (New et al 1977), and Gordon's syndrome (PHA2).…”

Section: Hypertension and Strokementioning

confidence: 99%

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Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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Human hypertension affects affects more than 20% of the adult population in industrialized countries, and it is implicated in millions of deaths worldwide each year from stroke, heart failure and ischemic heart disease. Available evidence suggests a major genetic impact on blood pressure regulation. Studies in monogenic hypertension revealed that renal salt and volume regulation systems are predominantly involved in the genesis of these disorders. Mutations here affect the synthesis of mineralocorticoids, the function of the mineralocorticoid receptor, epithelial sodium channels and their regulation by a new class of kinases, termed WNK kinases. It has been learned from monogenic hypotension that almost all ion transporters involved in the renal uptake of Na + have a major impact on blood pressure regulation. For essential hypertension as a complex disease, many candidate genes have been analysed. These include components of the reninangiotensin-aldosterone system, adducin, β-adrenoceptors, G protein subunits, regulators of G protein signalling (RGS) proteins, Rho kinases and G protein receptor kinases. At present, the individual impact of common polymorphisms in these genes on the observed blood pressure variation, on risk for stroke and as predictors of antihypertensive responses remains small and clinically irrelevant. Nevertheless, these studies have greatly augmented our knowledge on the regulation of renal functions, cellular signal transduction and the integration of both. Together, this provides the basis for the identification of novel drug targets and, hopefully, innovative antihypertensive drugs.

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Section: Autosomal Dominant Hypertension With Brachydactylymentioning

confidence: 99%

Section: Hypertension and Strokementioning

confidence: 99%

Genetics of arterial hypertension and hypotension

Rosskopf

Schürks

Rimmbach

et al. 2007

Naunyn-Schmied Arch Pharmacol

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“…5 The sole exception is autosomal-dominant hypertension with BDE (HTNB, OMIM #112410), first reported in a Turkish kindred. 2,6 HTNB was linked to chromosome 12p in six unrelated families. 2,7,8 The locus accounts for a ~50 mm Hg mean blood pressure difference at age 50 years.…”

mentioning

confidence: 99%

PDE3A mutations cause autosomal dominant hypertension with brachydactyly

et al. 2015

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All Mendelian hypertension syndromes described to date involve increased sodium reabsorption in the distal nephron. 5 The sole exception is autosomal-dominant hypertension with BDE (HTNB, OMIM #112410), first reported in a Turkish kindred. 2,6 HTNB was linked to chromosome 12p in six unrelated families. 2,7,8 The locus accounts for a ~50 mm Hg mean blood pressure difference at age 50 years. 2 The penetrance is 100% (Fig. 1a). Previously, we reported a rearrangement on chromosome 12p common to all families. 8,9 A linkage study in Chinese hypertensive families without BDE coincided with the HTNB locus, supporting relevance to essential hypertension. 10 Whole-genome sequencing of Turkish family members revealed a heterozygous missense mutation in PDE3A (Gene ID: 5139), a gene encoding a cGMP/cAMP phosphodiesterase with a prominent role in the heart, VSMC, oocytes and platelets. 11 Resequencing of all 48 affected persons in six unrelated families identified six independently clustered heterozygous missense mutations in exon 4 (Fig. 1a, b Supplementary Fig. 1).We detected none of the previously described chromosomal breakpoints on chromosome 12p12.2-12.1, perhaps due to high repetitive content in the breakpoint regions Fig. 2a-c). 4 A haplotype analysis identified a novel recombination that reduced the linkage interval and eliminated an inversion common to all affected individuals in the six families (Fig. 2c). 9 In contrast, the affected mother's haplotype showed co-segregation with the more severe brachydactyly phenotype.PDEs are involved during early stages of osteogenesis. 12 PDE4D mutations have been associated with severe brachydactyly in acrodysostosis. 13,14 In mice, Pde3a was expressed in the developing limbs, consistent with a role during chondrogenesis (Fig. 2d, Supplementary Fig. 3a, b). Chondrogenic downregulation of PTHLH encoding PTHrP was associated with BDE. 15 We also observed PTHLH downregulation in chondrogenically induced fibroblasts from affected persons (Fig. 2e, Supplementary Fig. 3c).We addressed the functional consequences of the identified PDE3A mutations in HeLa cells expressing the six mutations. Forskolin or L-arginine stimulated the adenylate or guanylate cyclases to enhance cellular cAMP or cGMP levels, respectively. 16,17 We detected significantly reduced cAMP levels, consistent with gain-of-function mutations with no change in cGMP levels for the PDE3A mutations ( Supplementary Fig. 4a, b). Three PDE3A isoforms, PDE3A1 (microsomal), PDE3A2 and PDE3A3 (microsomal and cytosolic), have been identified in human myocardium. 18,19 PDE3A3 does not contain the sequence harboring the detected mutations. The predominant isoform in VSMC is PDE3A2. 18,20 To directly elucidate the mutations' effects, we compared the Michaelis-Menten kinetics of cAMPhydrolytic activity for recombinant T445N FLAG-tagged PDE3A1 and PDE3A1-WT and the tagged A2 isoforms purified from transfected cells (Fig. 3a, b, Supplementary Fig. 4d-k). The T445N mutation increased the affinity of both enzyme's isoforms for cAM...

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“…Bilginturan et al 1 first described the syndrome of severe autosomal dominant hypertension and brachydactyly. 1 The gene responsible for the syndrome was mapped to chromosome 12 p. 2 Magnetic resonance tomography showed that all 15 affected family members tested had a left-sided loop of the posterior inferior cerebellar artery (PICA) impinging on the rostral ventrolateral medulla, compared to none of 11 non-affected family members.…”

Section: Introductionmentioning

confidence: 99%

“…1 The gene responsible for the syndrome was mapped to chromosome 12 p. 2 Magnetic resonance tomography showed that all 15 affected family members tested had a left-sided loop of the posterior inferior cerebellar artery (PICA) impinging on the rostral ventrolateral medulla, compared to none of 11 non-affected family members. 3 Animal studies have shown that pulsatile compression of the rostral ventrolateral medulla increases blood pressure.…”

Section: Introductionmentioning

confidence: 99%

Autonomic nervous system function in patients with monogenic hypertension and brachydactyly: a field study in north-eastern Turkey

Tank

Toka

et al. 2001

J Hum Hypertens

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Laboratory studies in patients with autosomal-dominant hypertension and brachydactyly showed increased sensitivity to sympathetic stimuli and severe abnormalities in baroreflex buffering. To further elucidate the mechanisms by which impaired baroreflex sensitivity could influence blood pressure (BP), we conducted autonomic testing under field conditions. We studied 17 hypertensive affected (13 to 48 years, BMI 22.7 ؎ 6.5 kg/m 2 , 160 ؎ 23/98 ؎ 15 mm Hg) and 12 normotensive non-affected (9 to 60 years, BMI 24.0 ؎ 4.7 kg/m 2 , 120 ؎ 16/70 ؎ 10 mm Hg) family members. Pulse intervals and finger BP were measured using the Portapres device. Valsalva ratio, the blood pressure overshoot during phase IV of the Valsalva manoeuver, the Ewing coefficient (RR30/15 ratio), and heart rate and BP variability were similar in affected and non-affected family members. Overall, baroreflex sensitivity calculated using the cross-

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Hereditary Brachydactyly Associated with Hypertension

Cited by 83 publications

References 1 publication

Genetics of arterial hypertension and hypotension

Genetics of arterial hypertension and hypotension

PDE3A mutations cause autosomal dominant hypertension with brachydactyly

Autonomic nervous system function in patients with monogenic hypertension and brachydactyly: a field study in north-eastern Turkey

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