lunes, 15 de septiembre de 2014

European Journal of Human Genetics - Clinical utility gene card for: familial hypomagnesemia with hypercalciuria and nephrocalcinosis with/without severe ocular involvement

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European Journal of Human Genetics - Clinical utility gene card for: familial hypomagnesemia with hypercalciuria and nephrocalcinosis with/without severe ocular involvement



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Clinical Utility Gene Card

European Journal of Human Genetics advance online publication 3 September 2014; doi: 10.1038/ejhg.2014.176

Clinical utility gene card for: familial hypomagnesemia with hypercalciuria and nephrocalcinosis with/without severe ocular involvement

Félix Claverie-Martín1, Rosa Vargas-Poussou2, Dominik Müller3 and Víctor García-Nieto4
  1. 1Unidad de Investigación, Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
  2. 2Département de Génétique, Hôpital Européen Georges Pompidou, Paris, France
  3. 3Department of Pediatric Nephrology, Charité, Berlin, Germany
  4. 4Unidad de Nefrología Pediátrica, Hospital Nuestra Señora de Candelaria, Santa Cruz de Tenerife, Spain
Correspondence: Dr F Claverie-Martín, Unidad de Investigación, Hospital Nuestra Señora de Candelaria, Carretera del Rosario 145, Santa Cruz de Tenerife 38010, Spain. Tel: +34 922 60 0546; Fax: +34 922 60 0562; E-mail: fclamar@gobiernodecanarias.org
Received 17 March 2014; Revised 28 June 2014; Accepted 13 July 2014
Advance online publication 3 September 2014
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1. DISEASE CHARACTERISTICS

1.1 Name of the disease (synonyms)

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC), primary hypomagnesemia, renal hypomagnesemia (caused by variants in CLDN16).
FHHNC with severe ocular involvement, renal hypomagnesemia with severe ocular involvement (caused by variants in CLDN19).

1.2 OMIM# of the disease

248250 (FHHNC) and 248190 (FHHNC with severe ocular involvement).

1.3 Name of the analysed genes or DNA/chromosome segments

CLDN16 (previously known as PCLN1) (locus 3q27), CLDN19 (locus 1p34.2).

1.4 OMIM# of the gene(s)

603959 (CLDN16), 610036 (CLDN19).

1.5 Mutational spectrum

Familial hypomagnesemia with hypercalciuria and nephrocalcinosis (FHHNC) and FHHNC with severe ocular involvement are autosomal recessive renal tubular disorders caused by variants in the CLDN16 (locus 3q27) and CLDN19 (locus 1p34.2) genes, respectively.12 These genes encode the tight-junction proteins claudin-16 (paracellin-1) and claudin-19, respectively, which are important for the paracellular reabsorption of calcium and magnesium in the thick ascending limb of Henle’s loop.3 Claudin-19 is also expressed in the retinal epithelium. FHHNC is characterized by excessive urinary losses of magnesium and calcium, nephrocalcinosis, kidney stones in about 1/3 of cases and progressive renal failure. Approximately one-third of patients progress to renal failure or end-stage renal disease (ESRD) during adolescence. In most cases, patients with CLDN19 variants additionally have severe ocular abnormalities (mainly myopia, nystagmus and macular colobomata).
Fifty-six CLDN16 disease-causing variants have been described so far.124567,891011121314 (see also HGMD: http://www.hgmd.org/). These include missense variants (41), nonsense variants (5), splice site variants (5), small deletions (3) and small indels (2). The majority of CLDN16 variants are spread over all the five exons. Missense variants are located in or near the four transmembrane domains, in the two extracellular loops or in the C-terminal cytoplasmic region. Variants in affected individuals occur in either homozygous or compound-heterozygous state. The most frequent CLDN16 disease-causing variant, c.453G>T (p.L151F), occurring in almost 50% of the patients described so far, is due to a widespread founder effect (Germany and Eastern European countries).4 A founder effect has been also detected for the recurrent disease-causing c.416C>T (p.A139V) variant in North African families.10

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