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A novel mutation of the HNF1B gene associated with hypoplastic glomerulocystic kidney disease and neonatal renal failure: a case report and mutation update.

Alvelos MI, Rodrigues M, Lobo L, Medeira A, Sousa AB, Simão C, Lemos MC - Medicine (Baltimore) (2015)

Bottom Line: A Portuguese 19-month-old male infant was evaluated due to hypoplastic glomerulocystic kidney disease and renal dysfunction diagnosed in the neonatal period that progressed to stage 5 chronic renal disease during the first year of life.His mother was diagnosed with a solitary hypoplastic microcystic left kidney at age 20, with stage 2 chronic renal disease established at age 35, and presented bicornuate uterus, pancreatic atrophy, and gestational diabetes.The study of this family with an unusual presentation of hypoplastic glomerulocystic kidney disease with neonatal renal dysfunction identified a previously unreported mutation of the HNF1B gene, thereby expanding the spectrum of known mutations associated with renal developmental disorders.

View Article: PubMed Central - PubMed

Affiliation: From the CICS-UBI, Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal (MIA, MCL); Paediatric Nephrology & Renal Transplantation Unit, Department of Paediatrics, Santa Maria Hospital, Lisbon, Portugal (MR, CS); Department of Radiology, Santa Maria Hospital, Lisbon, Portugal (LL); and Genetics Unit, Department of Paediatrics, Santa Maria Hospital, Lisbon, Portugal (AM, ABS).

ABSTRACT
Hepatocyte nuclear factor 1 beta (HNF1B) plays an important role in embryonic development, namely in the kidney, pancreas, liver, genital tract, and gut. Heterozygous germline mutations of HNF1B are associated with the renal cysts and diabetes syndrome (RCAD). Affected individuals may present a variety of renal developmental abnormalities and/or maturity-onset diabetes of the young (MODY). A Portuguese 19-month-old male infant was evaluated due to hypoplastic glomerulocystic kidney disease and renal dysfunction diagnosed in the neonatal period that progressed to stage 5 chronic renal disease during the first year of life. His mother was diagnosed with a solitary hypoplastic microcystic left kidney at age 20, with stage 2 chronic renal disease established at age 35, and presented bicornuate uterus, pancreatic atrophy, and gestational diabetes. DNA sequence analysis of HNF1B revealed a novel germline frameshift insertion (c.110_111insC or c.110dupC) in both the child and the mother. A review of the literature revealed a total of 106 different HNF1B mutations, in 236 mutation-positive families, comprising gross deletions (34%), missense mutations (31%), frameshift deletions or insertions (15%), nonsense mutations (11%), and splice-site mutations (8%). The study of this family with an unusual presentation of hypoplastic glomerulocystic kidney disease with neonatal renal dysfunction identified a previously unreported mutation of the HNF1B gene, thereby expanding the spectrum of known mutations associated with renal developmental disorders.

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Identification of a germline frameshift insertion or duplication (c.110_111insC or c.110dupC) in the HNF1B gene in affected family members. (A) Pedigree of the family affected with hypoplastic glomerulocystic kidney disease, with the proband (III-5) indicated by an arrow. Individuals are represented as men (squares), women (circles), unaffected (open symbol), affected (filled symbol), deceased (oblique line through symbol), and miscarriages (triangles). (B) DNA sequence of the PCR product obtained from the proband, showing evidence of a heterozygous frameshift mutation. (C) DNA sequence of the normal allele, obtained through pGEM-T cloning of the PCR product from the proband. (D) DNA sequence of the mutated allele, obtained through pGEM-T cloning, showing the insertion (or duplication) of the additional cytosine (asterisk). (E) Agarose gel electrophoresis of a multiplex PCR using a 3’ modified forward primer complementary to the mutated allele. The affected individuals (II-2 and III-5) show a lower band (330 base pairs) corresponding to the amplification of the mutated allele, whereas this band is absent in the maternal grandmother (I-2) and in four normal controls (N). The upper band (529 base pairs) is an internal PCR control that results from amplification of exon 1. A 100 base-pair ladder molecular-weight marker (m) is shown. The mutation (c.110_111insC or c.110dupC) is numbered in relation to the HNF1B cDNA reference sequence (GenBank accession number NM_000458.2), whereby nucleotide +1 corresponds to the A of the ATG-translation initiation codon.
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Figure 2: Identification of a germline frameshift insertion or duplication (c.110_111insC or c.110dupC) in the HNF1B gene in affected family members. (A) Pedigree of the family affected with hypoplastic glomerulocystic kidney disease, with the proband (III-5) indicated by an arrow. Individuals are represented as men (squares), women (circles), unaffected (open symbol), affected (filled symbol), deceased (oblique line through symbol), and miscarriages (triangles). (B) DNA sequence of the PCR product obtained from the proband, showing evidence of a heterozygous frameshift mutation. (C) DNA sequence of the normal allele, obtained through pGEM-T cloning of the PCR product from the proband. (D) DNA sequence of the mutated allele, obtained through pGEM-T cloning, showing the insertion (or duplication) of the additional cytosine (asterisk). (E) Agarose gel electrophoresis of a multiplex PCR using a 3’ modified forward primer complementary to the mutated allele. The affected individuals (II-2 and III-5) show a lower band (330 base pairs) corresponding to the amplification of the mutated allele, whereas this band is absent in the maternal grandmother (I-2) and in four normal controls (N). The upper band (529 base pairs) is an internal PCR control that results from amplification of exon 1. A 100 base-pair ladder molecular-weight marker (m) is shown. The mutation (c.110_111insC or c.110dupC) is numbered in relation to the HNF1B cDNA reference sequence (GenBank accession number NM_000458.2), whereby nucleotide +1 corresponds to the A of the ATG-translation initiation codon.

Mentions: A 19-month-old male infant, first born child of nonconsanguineous Portuguese parents, was evaluated due to renal cysts and progressive renal disease diagnosed in the neonatal period. Pregnancy was complicated by maternal diabetes and chronic renal disease (CRD), and prenatal ultrasonography at 33 weeks’ gestation revealed hydramnios and large hyperechogenic kidneys. He was born by cesarean section performed at 35 weeks due to deteriorating maternal renal function. Apgar score at birth was normal, and weight and length were normal for gestational age. In the neonatal period, he was found to have elevated serum levels of creatinine, urea, and phosphorus, and a reduced glomerular filtration rate (GFR) (Table 1). Postnatal renal ultrasonography revealed slightly enlarged kidneys (longitudinal diameter: right 53 mm and left 51 mm), absence of corticomedullary differentiation, and diffuse hyperechogenicity with the presence of bilateral multiple small (≤5 mm) renal cysts with predominantly subcortical distribution. Careful evaluation did not identify any extra-renal malformations. The child was maintained under conservative therapy with nutritional management and dietary phosphate and potassium restriction, dietary phosphate binders, calcitriol, and folic acid, with dose adjustments according to blood chemistry results. During the first year of life, renal function impairment remained at stage 5 CRD (Table 1). At 1 year of age, renal ultrasonography showed kidney sizes smaller than expected for age (right 52 mm and left 55 mm), and with the same features as above (Figure 1). At 16 months of age, during an upper respiratory infection, renal function deteriorated, requiring initiation of substitutive therapy by peritoneal dialysis. No evidence for diabetes mellitus in the infant was found to date, as assessed by fasting plasma glucose and glycated hemoglobin (HbA1c). His mother, who was 34 years old at the time of birth, had been diagnosed with a solitary hypoplastic microcystic left kidney at age 20, with stage 2 CRD established at age 35. Additional investigations showed that she had extra-renal malformations, namely bicornuate uterus and atrophy of the body and tail of the pancreas. No history of diabetes mellitus was elicited, except for diet-treated gestational diabetes diagnosed at 25 weeks, with remission after delivery. She had a history of four previous miscarriages, but it was not possible to determine if the latter were due to her uterine abnormalities or corresponded to severely affected fetuses. There was no history of renal disease or diabetes in the maternal grandparents (Figure 2A).


A novel mutation of the HNF1B gene associated with hypoplastic glomerulocystic kidney disease and neonatal renal failure: a case report and mutation update.

Alvelos MI, Rodrigues M, Lobo L, Medeira A, Sousa AB, Simão C, Lemos MC - Medicine (Baltimore) (2015)

Identification of a germline frameshift insertion or duplication (c.110_111insC or c.110dupC) in the HNF1B gene in affected family members. (A) Pedigree of the family affected with hypoplastic glomerulocystic kidney disease, with the proband (III-5) indicated by an arrow. Individuals are represented as men (squares), women (circles), unaffected (open symbol), affected (filled symbol), deceased (oblique line through symbol), and miscarriages (triangles). (B) DNA sequence of the PCR product obtained from the proband, showing evidence of a heterozygous frameshift mutation. (C) DNA sequence of the normal allele, obtained through pGEM-T cloning of the PCR product from the proband. (D) DNA sequence of the mutated allele, obtained through pGEM-T cloning, showing the insertion (or duplication) of the additional cytosine (asterisk). (E) Agarose gel electrophoresis of a multiplex PCR using a 3’ modified forward primer complementary to the mutated allele. The affected individuals (II-2 and III-5) show a lower band (330 base pairs) corresponding to the amplification of the mutated allele, whereas this band is absent in the maternal grandmother (I-2) and in four normal controls (N). The upper band (529 base pairs) is an internal PCR control that results from amplification of exon 1. A 100 base-pair ladder molecular-weight marker (m) is shown. The mutation (c.110_111insC or c.110dupC) is numbered in relation to the HNF1B cDNA reference sequence (GenBank accession number NM_000458.2), whereby nucleotide +1 corresponds to the A of the ATG-translation initiation codon.
© Copyright Policy - open-access
Related In: Results  -  Collection

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Show All Figures
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Figure 2: Identification of a germline frameshift insertion or duplication (c.110_111insC or c.110dupC) in the HNF1B gene in affected family members. (A) Pedigree of the family affected with hypoplastic glomerulocystic kidney disease, with the proband (III-5) indicated by an arrow. Individuals are represented as men (squares), women (circles), unaffected (open symbol), affected (filled symbol), deceased (oblique line through symbol), and miscarriages (triangles). (B) DNA sequence of the PCR product obtained from the proband, showing evidence of a heterozygous frameshift mutation. (C) DNA sequence of the normal allele, obtained through pGEM-T cloning of the PCR product from the proband. (D) DNA sequence of the mutated allele, obtained through pGEM-T cloning, showing the insertion (or duplication) of the additional cytosine (asterisk). (E) Agarose gel electrophoresis of a multiplex PCR using a 3’ modified forward primer complementary to the mutated allele. The affected individuals (II-2 and III-5) show a lower band (330 base pairs) corresponding to the amplification of the mutated allele, whereas this band is absent in the maternal grandmother (I-2) and in four normal controls (N). The upper band (529 base pairs) is an internal PCR control that results from amplification of exon 1. A 100 base-pair ladder molecular-weight marker (m) is shown. The mutation (c.110_111insC or c.110dupC) is numbered in relation to the HNF1B cDNA reference sequence (GenBank accession number NM_000458.2), whereby nucleotide +1 corresponds to the A of the ATG-translation initiation codon.
Mentions: A 19-month-old male infant, first born child of nonconsanguineous Portuguese parents, was evaluated due to renal cysts and progressive renal disease diagnosed in the neonatal period. Pregnancy was complicated by maternal diabetes and chronic renal disease (CRD), and prenatal ultrasonography at 33 weeks’ gestation revealed hydramnios and large hyperechogenic kidneys. He was born by cesarean section performed at 35 weeks due to deteriorating maternal renal function. Apgar score at birth was normal, and weight and length were normal for gestational age. In the neonatal period, he was found to have elevated serum levels of creatinine, urea, and phosphorus, and a reduced glomerular filtration rate (GFR) (Table 1). Postnatal renal ultrasonography revealed slightly enlarged kidneys (longitudinal diameter: right 53 mm and left 51 mm), absence of corticomedullary differentiation, and diffuse hyperechogenicity with the presence of bilateral multiple small (≤5 mm) renal cysts with predominantly subcortical distribution. Careful evaluation did not identify any extra-renal malformations. The child was maintained under conservative therapy with nutritional management and dietary phosphate and potassium restriction, dietary phosphate binders, calcitriol, and folic acid, with dose adjustments according to blood chemistry results. During the first year of life, renal function impairment remained at stage 5 CRD (Table 1). At 1 year of age, renal ultrasonography showed kidney sizes smaller than expected for age (right 52 mm and left 55 mm), and with the same features as above (Figure 1). At 16 months of age, during an upper respiratory infection, renal function deteriorated, requiring initiation of substitutive therapy by peritoneal dialysis. No evidence for diabetes mellitus in the infant was found to date, as assessed by fasting plasma glucose and glycated hemoglobin (HbA1c). His mother, who was 34 years old at the time of birth, had been diagnosed with a solitary hypoplastic microcystic left kidney at age 20, with stage 2 CRD established at age 35. Additional investigations showed that she had extra-renal malformations, namely bicornuate uterus and atrophy of the body and tail of the pancreas. No history of diabetes mellitus was elicited, except for diet-treated gestational diabetes diagnosed at 25 weeks, with remission after delivery. She had a history of four previous miscarriages, but it was not possible to determine if the latter were due to her uterine abnormalities or corresponded to severely affected fetuses. There was no history of renal disease or diabetes in the maternal grandparents (Figure 2A).

Bottom Line: A Portuguese 19-month-old male infant was evaluated due to hypoplastic glomerulocystic kidney disease and renal dysfunction diagnosed in the neonatal period that progressed to stage 5 chronic renal disease during the first year of life.His mother was diagnosed with a solitary hypoplastic microcystic left kidney at age 20, with stage 2 chronic renal disease established at age 35, and presented bicornuate uterus, pancreatic atrophy, and gestational diabetes.The study of this family with an unusual presentation of hypoplastic glomerulocystic kidney disease with neonatal renal dysfunction identified a previously unreported mutation of the HNF1B gene, thereby expanding the spectrum of known mutations associated with renal developmental disorders.

View Article: PubMed Central - PubMed

Affiliation: From the CICS-UBI, Health Sciences Research Centre, Faculty of Health Sciences, University of Beira Interior, Covilhã, Portugal (MIA, MCL); Paediatric Nephrology & Renal Transplantation Unit, Department of Paediatrics, Santa Maria Hospital, Lisbon, Portugal (MR, CS); Department of Radiology, Santa Maria Hospital, Lisbon, Portugal (LL); and Genetics Unit, Department of Paediatrics, Santa Maria Hospital, Lisbon, Portugal (AM, ABS).

ABSTRACT
Hepatocyte nuclear factor 1 beta (HNF1B) plays an important role in embryonic development, namely in the kidney, pancreas, liver, genital tract, and gut. Heterozygous germline mutations of HNF1B are associated with the renal cysts and diabetes syndrome (RCAD). Affected individuals may present a variety of renal developmental abnormalities and/or maturity-onset diabetes of the young (MODY). A Portuguese 19-month-old male infant was evaluated due to hypoplastic glomerulocystic kidney disease and renal dysfunction diagnosed in the neonatal period that progressed to stage 5 chronic renal disease during the first year of life. His mother was diagnosed with a solitary hypoplastic microcystic left kidney at age 20, with stage 2 chronic renal disease established at age 35, and presented bicornuate uterus, pancreatic atrophy, and gestational diabetes. DNA sequence analysis of HNF1B revealed a novel germline frameshift insertion (c.110_111insC or c.110dupC) in both the child and the mother. A review of the literature revealed a total of 106 different HNF1B mutations, in 236 mutation-positive families, comprising gross deletions (34%), missense mutations (31%), frameshift deletions or insertions (15%), nonsense mutations (11%), and splice-site mutations (8%). The study of this family with an unusual presentation of hypoplastic glomerulocystic kidney disease with neonatal renal dysfunction identified a previously unreported mutation of the HNF1B gene, thereby expanding the spectrum of known mutations associated with renal developmental disorders.

Show MeSH
Related in: MedlinePlus