Urinary Tract Effects of HPSE2 Mutations

Stuart, Helen M.; Roberts, Neil; Hilton, Emma; McKenzie, Edward A.; Daly, Sarah B.; Hadfield, Kristen D.; Rahal, Jeffery S; Gardiner, Natalie J.; Tanley, S.W.M.; Lewis, Malcolm; Sites, Emily; Angle, Brad; Alves, Cláudia; Lourenço, Teresa; Rodrigues, Márcia; Calado, Angelina; Amadó, Marta Perapoch; Guerreiro, Nancy; Serras, Inês; Beetz, Christian; Varga, Rita-Eva; Sılay, Mesrur Selçuk; Darlow, John M; Dobson, Mark G; Barton, D. E.; Hunziker, Manuela; Puri, Prem; Feather, Sally; Goodship, Judith A.; Goodship, Timothy H.J.; Lambert, H; Cordell, Heather J.; Saggar, Anand; Kinali, Maria; Lorenz, Christian; Moeller, Kristina; Schaefer, Franz; Bayazıt, Aysun Karabay; Weber, Stefanie; Newman, William G.; Woolf, Adrian S.

doi:10.1681/asn.2013090961

Cited by 40 publications

(80 citation statements)

References 27 publications

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“…The nonsense mutation in HPSE2 gene of our patient has been formerly defined in two Turkish brothers (8). They both had large trabeculated bladder without VUR and one also had high Scr as in our patient.…”

Section: Discussionsupporting

confidence: 59%

See 1 more Smart Citation

Chronic Kidney Disease in a Boy with Enuresis: The Diagnosis Behind the Smile

Demir

Hall²,

Newman³

2017

Turk Neph Dial Transpl

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A 13-year-old boy was admitted with enuresis. He had no history of urinary tract infection, daytime incontinence or fecal incontinence. Previously performed ultrasound had revealed bilateral hydroureteronephrosis and trabeculated bladder. Voiding cystoureterography had detected multiple diverticuli without reflux. Renal scan had revealed reduced uptake with multiple renal scarring and diuretic renogram had shown bilateral obstruction. Urodynamic evaluation had revealed non-compliant hyperactive bladder and significant residual volume. Laboratory tests had been consistent with chronic kidney disease and he had been referred to our clinic. On admission, he was diagnosed with urofacial syndrome, due to the grimacing expression while trying to smile on physical examination, and the diagnosis was further confirmed by genetic analysis during follow-up. This case was reported to increase the awareness of physicians about this rare cause of chronic kidney disease as early diagnosis is mandatory. Asking the patient to smile would easily lead to the diagnosis.Key WORdS: Urofacial syndrome, Chronic kidney disease, Enuresis, Children ÖzOn üç yaşında erkek olgu geceleri idrar kaçırma şikayeti ile başvurdu. Geçirilmiş idrar yolu enfeksiyonu, gündüz idrar kaçırma ya da dışkı kaçırma gibi şikayetlerinin olmadığını belirtti. Başvuru öncesi yapılan ultrasonografisinde bilateral hidroüreteronefrozunun olduğu ve mesanesinin trabeküle olduğu görüldü. İşeme sistoüretrogramında reflüsünün olmadığı ancak çoklu divertiküllerinin olduğu gözlendi. Diüretik renogramında bilateral obstrüksiyonu izlendi. Ürodinamik değerlendirmede kompliyansı düşük hiperaktif mesanesinin olduğu ve anlamlı miktarda rezidüel idrarının kaldığı görüldü. Laboratuvar testlerinin kronik böbrek hastalığı ile uyumlu olması üzerine olgu kliniğimize yönlendirildi. Başvurusunda olgunun fizik bakısında gülmeye çalışırken yüzünde gelişen ağlama/buruşma ifadesi nedeni ile ürofasyal sendrom tanısı aldı ve izleminde tanısı genetik olarak doğrulandı. Olgu, erken tanının önemli olduğu son dönem böbrek yetmezliğinin nadir nedenlerinden olan ürofasyal sendrom konusunda hekimlerin farkındalığını arttırmak amacı ile sunulmuştur. Hastadan sadece gülümsemesini istemek kolaylıkla tanıya götürmektedir.aNaHtaR SÖzCüKleR: Ürofasyal sendrom, Böbrek yetmezliği, Enürezis, Çocuk

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Section: Discussionsupporting

confidence: 59%

“…Some others proposed that two separate lesions affecting facial nerve nucleus and sacral cord motor nuclei innervating the external sphincter were responsible (6). The most recent studies in animal models indicate a peripheral autonomic neuropathy for BD in UFS (7,8).…”

Section: Discussionmentioning

confidence: 99%

Chronic Kidney Disease in a Boy with Enuresis: The Diagnosis Behind the Smile

Demir

Hall²,

Newman³

2017

Turk Neph Dial Transpl

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“…Thus, these mutations may be responsible for other bladder diseases like NNNB or severe LUTD. Very recently, Stuart et al screened LRIG2 and HPSE2 mutations in 23 patients with NNNB and found potentially pathogenic variants in LRIG2 in only one case [17,24]. Likewise, in our study we did not find HPSE2 mutations in patients with NNNB and severe LUTD.…”

Section: Discussionsupporting

confidence: 54%

<b><i>HPSE2</i></b> Mutations in Urofacial Syndrome, Non-Neurogenic Neurogenic Bladder and Lower Urinary Tract Dysfunction

Bulum

Özçakar

Duman

et al. 2015

Nephron

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Background: Urofacial syndrome (UFS) is characterised by congenital bladder dysfunction accompanied by a characteristic abnormal grimace upon smiling and crying. In recent years, biallelic mutations of HPSE2 and LRIG2 have been reported in UFS patients. Non-neurogenic neurogenic bladder (NNNB) has a bladder identical to UFS without typical facial features. The aim of this study was to analyse HPSE2 mutations in patients with UFS and NNNB or severe lower urinary tract dysfunction (LUTD) without abnormal facial expression. Methods: Patients with UFS, NNNB and severe LUTD were enrolled in the study. We examined a total of 35 patients from 33 families. There were seven UFS patients from five different families, 21 patients with NNNB and seven with LUTD. HPSE2 gene mutation analysis was performed using the polymerase chain reaction protocol followed by Sanger sequencing in these patients. Results: A twin pair with UFS was found to be homozygous for c.457C>T (p.Arg153*) mutation. No other pathogenetic variant was detected. Conclusion:HPSE2 mutations were found in one UFS family but not detected in patients with NNNB and severe LUTD. Considering the increasingly recognised cases of NNNB that were diagnosed in early childhood period, genetic factors appear to be responsible. Thus, further genetic studies are needed to discover novel associated gene variants in these bladder anomalies.

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“…This congenital disorder features somatic motor neuropathy, obvious in the face but occasionally more widespread, and an autonomic neuropathy causing bladder dysfunction leading to renal failure (41). Notably, biallelic mutation in the HPSE2 gene is held responsible for some cases of UFS in families from different ethnic groups (42–44), resulting in frameshift or nonsense, postulated functionally null, Hpa2 variants (45). Moreover, mice carrying mutant Hpa2 exhibit bladder dysfunction (44, 46), associating with increased bladder fibrosis (46).…”

Section: Discussionmentioning

confidence: 99%

“…Notably, biallelic mutation in the HPSE2 gene is held responsible for some cases of UFS in families from different ethnic groups (42–44), resulting in frameshift or nonsense, postulated functionally null, Hpa2 variants (45). Moreover, mice carrying mutant Hpa2 exhibit bladder dysfunction (44, 46), associating with increased bladder fibrosis (46). The relevance of our findings with Hpa2 over expressing head and neck carcinoma cells (i.e., increased cell differentiation, neurogenesis, LOX expression) to UFS and the lethality phenotype of Hpa2 mutant mice (46) are yet to be resolved.…”

Section: Discussionmentioning

confidence: 99%

Heparanase 2 Attenuates Head and Neck Tumor Vascularity and Growth

et al. 2016

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The endoglycosidase heparanase specifically cleaves the heparan sulfate (HS) side chains on proteoglycans, an activity that has been implicated strongly in tumor metastasis and angiogenesis. Heparanase-2 (Hpa2) is a close homolog of heparanase that lacks intrinsic HS-degrading activity but retains the capacity to bind HS with high affinity. In head and neck cancer patients, Hpa2 expression was markedly elevated, correlating with prolonged time to disease recurrence and inversely correlating with tumor cell dissemination to regional lymph nodes, suggesting that Hpa2 functions as a tumor suppressor. The molecular mechanism associated with favorable prognosis following Hpa2 induction is unclear. Here we provide evidence that Hpa2 overexpression in head and neck cancer cells markedly reduces tumor growth. Restrained tumor growth was associated with a prominent decrease in tumor vascularity (blood and lymph vessels), likely due to reduced Id1 expression, a transcription factor highly implicated in VEGF-A and VEGF-C gene regulation. We also noted that tumors produced by Hpa2 overexpressing cells are abundantly decorated with stromal cells and collagen deposition, correlating with a marked increase in lysyl oxidase expression. Notably, heparanase enzymatic activity was unimpaired in cells overexpressing Hpa2, suggesting that reduced tumor growth is not caused by heparanase regulation. Moreover, growth of tumor xenografts by Hpa2-overexpressing cells was unaffected by administration of a monoclonal antibody that targets the heparin binding domain of Hpa2, implying that Hpa2 function does not rely on heparanase or heparin sulfate

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Urinary Tract Effects of HPSE2 Mutations

Cited by 40 publications

References 27 publications

Chronic Kidney Disease in a Boy with Enuresis: The Diagnosis Behind the Smile

Chronic Kidney Disease in a Boy with Enuresis: The Diagnosis Behind the Smile

<b><i>HPSE2</i></b> Mutations in Urofacial Syndrome, Non-Neurogenic Neurogenic Bladder and Lower Urinary Tract Dysfunction

Heparanase 2 Attenuates Head and Neck Tumor Vascularity and Growth

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