Neonatal Diabetes Mellitus and Neonatal Polycystic, Dysplastic Kidneys: Phenotypically Discordant Recurrence of a Mutation in the Hepatocyte Nuclear Factor-1β Gene Due to Germline Mosaicism

Yorifuji, Tohru; Kurokawa, Keiji; Mamada, Mitsukazu; Imai, Tsuyoshi; Kawai, Masahiko; Nishi, Yoshikazu; Shishido, Seiichiro; Hasegawa, Yukihiro; Nakahata, Tatsutoshi

doi:10.1210/jc.2003-031828

Cited by 110 publications

(89 citation statements)

References 21 publications

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“…This result shows that molecular testing must be performed, even when there is no known family history. In these cases, families can be reassured regarding the risk of recurrence for future pregnancies, which is limited to the low risk of germinal mosaicism (22).…”

Section: Discussionmentioning

confidence: 99%

Severe Prenatal Renal Anomalies Associated with Mutations in HNF1B or PAX2 Genes

Madariaga¹,

Morinière²,

Jeanpierre³

et al. 2013

Clinical Journal of the American Society of Nephrology

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SummaryBackground and objectives Congenital anomalies of the kidney and urinary tract (CAKUT) are a frequent cause of renal failure in children, and their detection in utero is now common with fetal screening ultrasonography. The clinical course of CAKUT detected before birth is very heterogeneous and depends on the level of nephron reduction. The most severe forms cause life-threatening renal failure, leading to perinatal death or the need for very early renal replacement therapy.Design, setting, participants, & measurements This study reports the screening of two genes (HNF1B and PAX2) involved in monogenic syndromic CAKUT in a cohort of 103 fetuses from 91 families with very severe CAKUT that appeared isolated by fetal ultrasound examination and led to termination of pregnancy.Results This study identified a disease-causing mutation in HNF1B in 12 cases from 11 families and a mutation in PAX2 in 4 unrelated cases. Various renal phenotypes were observed, but no case of bilateral agenesis was associated with HNF1B or PAX2 mutations. Autopsy identified extrarenal abnormalities not detected by ultrasonography in eight cases but confirmed the absence of extrarenal defects in eight other cases. A positive family history of renal disease was not significantly more frequent in cases with an identified mutation. Moreover, in cases with an inherited mutation, there was a great phenotypic variability regarding the severity of the renal disease within a single family. ConclusionsOur results suggest that mutations in genes involved in syndromic CAKUT with Mendelian inheritance are not rare in fetal cases with severe CAKUT appearing isolated at prenatal ultrasound, a finding of clinical importance because of genetic counseling.

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Section: Discussionmentioning

confidence: 99%

Severe Prenatal Renal Anomalies Associated with Mutations in HNF1B or PAX2 Genes

Madariaga¹,

Morinière²,

Jeanpierre³

et al. 2013

Clinical Journal of the American Society of Nephrology

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“…This finding is consistent with TNDM resulting from a less severe insulin deficiency, and is comparable to the situation with mutations in the Kir6.2 subunit of the K ATP mutations (38), where TNDM mutations have less severe functional consequences. The mechanism of remission in recessive INS mutation carriers is not understood but is likely to reflect a variation in demand or the ability of the beta cell to meet this demand, as a similar timing of remission is seen in some patients with less severe mutations, resulting in channelopathies (14,38) and pancreatic developmental defects (39,40).…”

Section: Discussionmentioning

confidence: 99%

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Garin

Edghill²,

Akerman³

et al. 2010

Proc. Natl. Acad. Sci. U.S.A.

190

219

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Heterozygous coding mutations in the INS gene that encodes preproinsulin were recently shown to be an important cause of permanent neonatal diabetes. These dominantly acting mutations prevent normal folding of proinsulin, which leads to beta-cell death through endoplasmic reticulum stress and apoptosis. We now report 10 different recessive INS mutations in 15 probands with neonatal diabetes. Functional studies showed that recessive mutations resulted in diabetes because of decreased insulin biosynthesis through distinct mechanisms, including gene deletion, lack of the translation initiation signal, and altered mRNA stability because of the disruption of a polyadenylation signal. A subset of recessive mutations caused abnormal INS transcription, including the deletion of the C1 and E1 cis regulatory elements, or three different single base-pair substitutions in a CC dinucleotide sequence located between E1 and A1 elements. In keeping with an earlier and more severe beta-cell defect, patients with recessive INS mutations had a lower birth weight (−3.2 SD score vs. −2.0 SD score) and were diagnosed earlier (median 1 week vs. 10 weeks) compared to those with dominant INS mutations. Mutations in the insulin gene can therefore result in neonatal diabetes as a result of two contrasting pathogenic mechanisms. Moreover, the recessively inherited mutations provide a genetic demonstration of the essential role of multiple sequence elements that regulate the biosynthesis of insulin in man. (8-12). In contrast, abnormalities in chromosome 6q24 are the most common cause of TNDM (13), followed by mutations in the KCNJ11 and ABCC8 genes (14). Despite these advances, the etiology of neonatal diabetes is still not known in at least 30% of patients with PNDM, suggesting other genetic causes are still to be found (9).Insulin is secreted from islet beta cells of the pancreas. Insufficient secretion of insulin results in hyperglycemia and diabetes, whereas excessive secretion results in hypoglycemia. Insulin biosynthesis and secretion are therefore tightly regulated to maintain blood glucose levels within a narrow physiological range. Extensive studies have dissected an array of cis sequence elements in the INS promoter region and their cognate DNA binding factors, which together ensure the cellular specificity and rate of INS transcription (15)(16)(17)(18)(19)(20)(21)(22). In addition, insulin biosynthesis is strongly dependent on posttranscriptional regulatory mechanisms, including the modulation of translation and stability (23-25). The latter is largely mediated through sequences located in the untranslated regions of INS transcripts (26-28).

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“…These observations should stimulate clinicians to explore endocrine pancreas function early in patients with TCF2 anomalies before transplantation and to propose tailor-made antirejection therapies (i.e., nondiabetogenic treatment). The varied spectrum of pediatric pathologies that are linked to HNF-1␤ is illustrated by the possibility of neonatal diabetes and early renal failure (18). Another benefit of MRI would be the visualization of pancreas and the search for pancreatic hypoplasia (14,23).…”

Section: Discussionmentioning

confidence: 99%

“…TCF2 adult patients have mild to moderate renal failure in the absence of diabetic nephropathy (18). Moreover, pancreatic atrophy, urogenital abnormalities, abnormal liver enzyme levels, and hyperuricemia are observed in patients with TCF2 mutations (12)(13)(14)19,20).…”

mentioning

confidence: 99%

Anomalies of the TCF2 Gene Are the Main Cause of Fetal Bilateral Hyperechogenic Kidneys

Decramer

Parant

Beaufils³

et al. 2007

Journal of the American Society of Nephrology

226

194

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Prenatal discovery of fetal bilateral hyperechogenic kidneys is very stressful for pregnant women and their family, and accurate diagnosis of the cause of the moderate forms of this pathology is very difficult. Hepatocyte nuclear factor-1␤ that is encoded by the TCF2 gene is involved in the embryonic development of the kidneys. Sixty-two pregnancies with fetal bilateral hyperechogenic kidneys including 25 fetuses with inaccurate diagnosis were studied. TCF2 gene anomalies were detected in 18 (29%) of these 62 patients, and 15 of these 18 patients presented a complete heterozygous deletion of the TCF2 gene. Family screening revealed de novo TCF2 anomalies in more than half of the patients. TCF2 anomalies were associated with normal amniotic fluid volume and normal-sized kidneys between ؊2 and ؉2 SD in all patients except for two sisters. Antenatal cysts were detected in 11 of 18 patients, unilaterally in eight of 11. After birth, cysts appeared during the first year (17 of 18), and in patients with antenatal cysts, the number increased and developed bilaterally with decreased renal growth. In these 18 patients, the GFR decreased with longer follow-up and was lower in patients with solitary functioning dysplastic kidney. Heterozygous deletion of the TCF2 gene is an important cause of fetal hyperechogenic kidneys in this study and showed to be linked with early disease expression. The renal phenotype and the postnatal evolution were extremely variable and need a prospective long-term follow-up. Extrarenal manifestations are frequent in TCF2-linked pathologies. Therefore, prenatal counseling and follow-up should be multidisciplinary.

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Neonatal Diabetes Mellitus and Neonatal Polycystic, Dysplastic Kidneys: Phenotypically Discordant Recurrence of a Mutation in the Hepatocyte Nuclear Factor-1β Gene Due to Germline Mosaicism

Cited by 110 publications

References 21 publications

Severe Prenatal Renal Anomalies Associated with Mutations in HNF1B or PAX2 Genes

Severe Prenatal Renal Anomalies Associated with Mutations in HNF1B or PAX2 Genes

Recessive mutations in the INS gene result in neonatal diabetes through reduced insulin biosynthesis

Anomalies of the TCF2 Gene Are the Main Cause of Fetal Bilateral Hyperechogenic Kidneys

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