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A young child with pseudohypoaldosteronism type II by a mutation of Cullin 3.

Tsuji S, Yamashita M, Unishi G, Takewa R, Kimata T, Isobe K, Chiga M, Uchida S, Kaneko K - BMC Nephrol (2013)

Bottom Line: Genetic analysis of WNK1 and WNK4 revealed no mutations.However, analysis of the CUL3 gene of the patient showed abnormal splicing caused by the modification of exon 9.In this patient, CUL3 was found to play a fundamental role in the regulation of blood pressure, potassium levels, and acid-base balance.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, Kansai Medical University, 2-5-1 Shin- machi, Hirakata- shi, Osaka 573 1010, Japan. tsujis@hirakata.kmu.ac.jp

ABSTRACT

Background: Pseudohypoaldosteronism type II (PHA II), also referred to as Gordon syndrome, is a rare renal tubular disease that is inherited in an autosomal manner. Though mutations in WNK1 and WNK4 partially account for this disorder, in 2012, 2 research groups showed that KLHL3 and CUL3 were the causative genes for PHA II. Here, we firstly report on the Japanese child of PHA II caused by a mutation of CUL 3.

Case presentation: The patient was a 3-year-old Japanese girl having healthy unrelated parents. She was initially observed to have hyperkalemia, hyperchloremia, metabolic acidosis, and hypertension. A close investigation led to the diagnosis of PHA II, upon which abnormal findings of laboratory examinations and hypertension were immediately normalized by administering thiazides. Genetic analysis of WNK1 and WNK4 revealed no mutations. However, analysis of the CUL3 gene of the patient showed abnormal splicing caused by the modification of exon 9. The patient is currently 17 years old and does not exhibit hypertension or any abnormal findings on laboratory examination.

Conclusions: In this patient, CUL3 was found to play a fundamental role in the regulation of blood pressure, potassium levels, and acid-base balance.

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Related in: MedlinePlus

Result of direct sequencing of DNA and mRNA and splicing assay. (a) Sequence analysis of Cullin 3 DNA in the index patient. In the patient (PT), the last guanine (G) of exon 9 of the Cullin 3 in the wild type (WT) was displaced to cytosine (C). (b) Sequence analysis of Cullin 3 mRNA in the index patient. In the wild type (WT), exon 8 is followed by exon 9 in Cullin 3 mRNA. In contrast, exon 10 is present just after exon 8 as exon 9 is skipped in the patient (PT). (c) Reverse Transcription Polymerase Chain Reaction (RT-PCR) of Cullin 3 mRNA in the index patient. RT-PCR of Cullin 3 mRNA demonstrated a smaller molecular weight band (390 bp) only in the patient (PT) in addition to the band (561bp) observed in the wild type (WT). The smaller band is considered a product of the skipping of exon 9.
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Figure 1: Result of direct sequencing of DNA and mRNA and splicing assay. (a) Sequence analysis of Cullin 3 DNA in the index patient. In the patient (PT), the last guanine (G) of exon 9 of the Cullin 3 in the wild type (WT) was displaced to cytosine (C). (b) Sequence analysis of Cullin 3 mRNA in the index patient. In the wild type (WT), exon 8 is followed by exon 9 in Cullin 3 mRNA. In contrast, exon 10 is present just after exon 8 as exon 9 is skipped in the patient (PT). (c) Reverse Transcription Polymerase Chain Reaction (RT-PCR) of Cullin 3 mRNA in the index patient. RT-PCR of Cullin 3 mRNA demonstrated a smaller molecular weight band (390 bp) only in the patient (PT) in addition to the band (561bp) observed in the wild type (WT). The smaller band is considered a product of the skipping of exon 9.

Mentions: The patient was a 3-year-old Japanese girl with healthy unrelated parents. Her perinatal history and past medical history were unremarkable. She was observed to have hyperkalemia, hyperchloremia, metabolic acidosis, and hypertension, when she was admitted to our hospital for the treatment of croup syndrome. An initial physical examination revealed normal growth, with a height of 95.5 cm (+0.3 standard deviation [SD]) and a body weight of 14.0 kg (+0.2 SD). The patient’s development was also normal. Her body temperature was 36.4°C. Chest auscultation revealed normal breathing sounds and a regular heart beat without murmurs. Examination of the patient’s blood and blood pressure revealed hyperkalemia (6.8 mEq/L), hyperchloremia (112 mEq/L), metabolic acidosis (pH, 7.248; HCO3-, 12.6 mEq/L), and hypertension (124/30 mmHg). The plasma renin activity (0.2 ng∙ml-1∙h-1) and plasma aldosterone concentration (25 pg/ml) were also low. A closer investigation led to the diagnosis of PHA II, and abnormal findings on laboratory examinations and hypertension were promptly normalized by the administration of thiazides. Subsequent genetic analysis of WNK1 and WNK4 revealed no mutations. The CUL3 gene of the patient, her parents, and her younger brother were analyzed in 2013, based on the report by Boyden et al.[4]. Abnormal splicing caused by modification of exon 9 was detected only in the patient (Figure 1a). The skipping of exon 9 at the mRNA level was further confirmed by sequence analysis (Figure 1b) and reverse-transcription PCR (Figure 1c). Because a mutation of CUL3 and manifestation of PHA II were not observed in the family members of the patient, in this case, the mutation was considered to be de novo. The patient is currently 17 years old and is healthy, with no hypertension or abnormal findings on laboratory examinations. The most recently recorded height and body weight of the patient were 155.6 cm (−0.4 SD) and 52.6 kg (−0.1 SD), respectively.


A young child with pseudohypoaldosteronism type II by a mutation of Cullin 3.

Tsuji S, Yamashita M, Unishi G, Takewa R, Kimata T, Isobe K, Chiga M, Uchida S, Kaneko K - BMC Nephrol (2013)

Result of direct sequencing of DNA and mRNA and splicing assay. (a) Sequence analysis of Cullin 3 DNA in the index patient. In the patient (PT), the last guanine (G) of exon 9 of the Cullin 3 in the wild type (WT) was displaced to cytosine (C). (b) Sequence analysis of Cullin 3 mRNA in the index patient. In the wild type (WT), exon 8 is followed by exon 9 in Cullin 3 mRNA. In contrast, exon 10 is present just after exon 8 as exon 9 is skipped in the patient (PT). (c) Reverse Transcription Polymerase Chain Reaction (RT-PCR) of Cullin 3 mRNA in the index patient. RT-PCR of Cullin 3 mRNA demonstrated a smaller molecular weight band (390 bp) only in the patient (PT) in addition to the band (561bp) observed in the wild type (WT). The smaller band is considered a product of the skipping of exon 9.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC3733749&req=5

Figure 1: Result of direct sequencing of DNA and mRNA and splicing assay. (a) Sequence analysis of Cullin 3 DNA in the index patient. In the patient (PT), the last guanine (G) of exon 9 of the Cullin 3 in the wild type (WT) was displaced to cytosine (C). (b) Sequence analysis of Cullin 3 mRNA in the index patient. In the wild type (WT), exon 8 is followed by exon 9 in Cullin 3 mRNA. In contrast, exon 10 is present just after exon 8 as exon 9 is skipped in the patient (PT). (c) Reverse Transcription Polymerase Chain Reaction (RT-PCR) of Cullin 3 mRNA in the index patient. RT-PCR of Cullin 3 mRNA demonstrated a smaller molecular weight band (390 bp) only in the patient (PT) in addition to the band (561bp) observed in the wild type (WT). The smaller band is considered a product of the skipping of exon 9.
Mentions: The patient was a 3-year-old Japanese girl with healthy unrelated parents. Her perinatal history and past medical history were unremarkable. She was observed to have hyperkalemia, hyperchloremia, metabolic acidosis, and hypertension, when she was admitted to our hospital for the treatment of croup syndrome. An initial physical examination revealed normal growth, with a height of 95.5 cm (+0.3 standard deviation [SD]) and a body weight of 14.0 kg (+0.2 SD). The patient’s development was also normal. Her body temperature was 36.4°C. Chest auscultation revealed normal breathing sounds and a regular heart beat without murmurs. Examination of the patient’s blood and blood pressure revealed hyperkalemia (6.8 mEq/L), hyperchloremia (112 mEq/L), metabolic acidosis (pH, 7.248; HCO3-, 12.6 mEq/L), and hypertension (124/30 mmHg). The plasma renin activity (0.2 ng∙ml-1∙h-1) and plasma aldosterone concentration (25 pg/ml) were also low. A closer investigation led to the diagnosis of PHA II, and abnormal findings on laboratory examinations and hypertension were promptly normalized by the administration of thiazides. Subsequent genetic analysis of WNK1 and WNK4 revealed no mutations. The CUL3 gene of the patient, her parents, and her younger brother were analyzed in 2013, based on the report by Boyden et al.[4]. Abnormal splicing caused by modification of exon 9 was detected only in the patient (Figure 1a). The skipping of exon 9 at the mRNA level was further confirmed by sequence analysis (Figure 1b) and reverse-transcription PCR (Figure 1c). Because a mutation of CUL3 and manifestation of PHA II were not observed in the family members of the patient, in this case, the mutation was considered to be de novo. The patient is currently 17 years old and is healthy, with no hypertension or abnormal findings on laboratory examinations. The most recently recorded height and body weight of the patient were 155.6 cm (−0.4 SD) and 52.6 kg (−0.1 SD), respectively.

Bottom Line: Genetic analysis of WNK1 and WNK4 revealed no mutations.However, analysis of the CUL3 gene of the patient showed abnormal splicing caused by the modification of exon 9.In this patient, CUL3 was found to play a fundamental role in the regulation of blood pressure, potassium levels, and acid-base balance.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Pediatrics, Kansai Medical University, 2-5-1 Shin- machi, Hirakata- shi, Osaka 573 1010, Japan. tsujis@hirakata.kmu.ac.jp

ABSTRACT

Background: Pseudohypoaldosteronism type II (PHA II), also referred to as Gordon syndrome, is a rare renal tubular disease that is inherited in an autosomal manner. Though mutations in WNK1 and WNK4 partially account for this disorder, in 2012, 2 research groups showed that KLHL3 and CUL3 were the causative genes for PHA II. Here, we firstly report on the Japanese child of PHA II caused by a mutation of CUL 3.

Case presentation: The patient was a 3-year-old Japanese girl having healthy unrelated parents. She was initially observed to have hyperkalemia, hyperchloremia, metabolic acidosis, and hypertension. A close investigation led to the diagnosis of PHA II, upon which abnormal findings of laboratory examinations and hypertension were immediately normalized by administering thiazides. Genetic analysis of WNK1 and WNK4 revealed no mutations. However, analysis of the CUL3 gene of the patient showed abnormal splicing caused by the modification of exon 9. The patient is currently 17 years old and does not exhibit hypertension or any abnormal findings on laboratory examination.

Conclusions: In this patient, CUL3 was found to play a fundamental role in the regulation of blood pressure, potassium levels, and acid-base balance.

Show MeSH
Related in: MedlinePlus