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Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC): compound heterozygous mutation in the claudin 16 (CLDN16) gene.

ABSTRACT: BACKGROUND: Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive disorder of renal calcium and magnesium wasting frequently complicated by progressive chronic renal failure in childhood or adolescence. METHODS: A 7 year old boy was investigated following the findings of marked renal insufficiency and nephrocalcinosis in his 18-month old sister. He too was found to have extensive nephrocalcinosis with increased fractional excretion of magnesium: 12.4% (<4%) and hypercalciuria: 5.7 mmol (< 2.5/24 hours). He had renal impairment, partial distal renal tubular acidosis and defective urinary concentrating ability. Therapy with thiazide diuretics and magnesium supplements failed to halt the progression of the disorder. Both children subsequently underwent renal transplantation. Both children's parents are unaffected and there is one unaffected sibling. RESULTS: Mutation analysis revealed 2 heterozygous mutations in the claudin 16 gene (CLDN16) in both affected siblings; one missense mutation in exon 4: C646T which results in an amino acid change Arg216Cys in the second extracellular loop of CLDN16 and loss of function of the protein and a donor splice site mutation which changes intron 4 consensus splice site from 'GT' to 'TT' resulting in decreased splice efficiency and the formation of a truncated protein with loss of 64 amino acids in the second extracellular loop. CONCLUSION: The mutations in CLDN16 in this kindred affect the second extra-cellular loop of claudin 16. The clinical course and molecular findings suggest complete loss of function of the protein in the 2 affected cases and highlight the case for molecular diagnosis in individuals with FHHNC.

SUBMITTER: Hampson G

PROVIDER: S-EPMC2562370 | biostudies-literature | 2008

REPOSITORIES: biostudies-literature

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Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC): compound heterozygous mutation in the claudin 16 (CLDN16) gene.

Hampson Geeta G Konrad Martin A MA Scoble John J

BMC nephrology 20080924

<h4>Background</h4>Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC) is an autosomal recessive disorder of renal calcium and magnesium wasting frequently complicated by progressive chronic renal failure in childhood or adolescence.<h4>Methods</h4>A 7 year old boy was investigated following the findings of marked renal insufficiency and nephrocalcinosis in his 18-month old sister. He too was found to have extensive nephrocalcinosis with increased fractional excretion of ma ...[more]

PMID: 18816383

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Project description:BACKGROUND:Sixty mutations of claudin 16 coding gene have been reported in familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) patients. Recent investigations revealed that a highly conserved glycine-leucine-tryptophan (115G-L-W117) motif in the first extracellular segment (ESC1) of claudin 16 might be essential for stabilization of the appropriately folded ECS1 structure and conservation of normal claudin 16 function. However, neither missense nor nonsense mutation has ever been described in this motif. Our study aimed at identifying mutations in a Chinese patient with FHHNC and exploring the association between genotype and phenotype. CASE PRESENTATION:A 33-year-old female presented with 4 years history of recurrent acute pyelonephritis without other notable past medical history. Her healthy parents, who aged 56 and 53 respectively, were second cousins, and her only sibling died from renal failure without definite cause at age 25. Renal ultrasound imaging demonstrated atrophic kidneys and bilateral nephrocalcinosis. The laboratory workup revealed impaired renal function (Stage CKD IV), hypocalcemia and mild hypomagnesemia, accompanied with marked renal loss of magnesium and hypercalciuria. During the follow-up, treatment with calcitriol and calcium but not with magnesium was difficult to achieve normal serum calcium levels, whereas her serum magnesium concentration fluctuated within normal ranges. In the end, the patient unavoidably reached ESRD at 36 years old. The clinical features and family history suggested the diagnosis of FHHNC. To make a definite diagnosis, we use whole-exome sequencing to identify the disease-causing mutations and Sanger sequencing to confirm the mutation co-segregation in the family. As a result, a novel homozygous mutation (c.346C?>?G, p.Leu116Val) in 115G-L-W117 motif of claudin 16 was identified. Her parents, grandmother and one of her cousins carried heterozygous p.Leu116Val, whereas 200 unrelated controls did not carry this mutation. CONCLUSIONS:We described a delayed diagnosis patient with FHHNC in the Chinese population and identified a novel missense mutation in the highly conserved 115G-L-W117 motif of claudin 16 for the first time. According to the reported data and the information deduced from 3D modeling, we speculate that this mutation probably reserve partial residual function which might be related to the slight phenotype of the patient.

Dataset Information

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC): compound heterozygous mutation in the claudin 16 (CLDN16) gene.

Publications

Familial hypomagnesaemia with hypercalciuria and nephrocalcinosis (FHHNC): compound heterozygous mutation in the claudin 16 (CLDN16) gene.

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