Two new large deletions of the AVPR2 gene causing nephrogenic diabetes insipidus and a review of previously published deletions

Anesi, Laura; Gemmis, Paola de; Galla, Daniela; Hladnik, Uroš

doi:10.1093/ndt/gfs359

Cited by 15 publications

(15 citation statements)

References 30 publications

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“…AVPR2 has been shown to cause 90% of cases of hereditary NDI [Anesi et al, ]. The lack of symptoms associated with NDI in our proband provides further support that NDI previously reported in two individuals with L1 syndrome are secondary to the contiguous deletions of AVPR2 and not related to L1CAM [Tegay et al, ; Knops et al, ].…”

Section: Discussionsupporting

confidence: 86%

“…Only two cases of L1CAM whole gene deletions have previously been reported [Kutsche et al, ; Knops et al, ]. Both of the reported deletions involved additional genes surrounding L1CAM , such as AVPR2 , a gene responsible for 90% of hereditary nephrogenic diabetes insipidus (NDI) cases, and PDZD4 [Anesi et al, ]. Here we report on a child with a novel de novo 62 kb deletion resulting in the loss of all of L1CAM and the first exon of PDZD4 .…”

Section: Introductionmentioning

confidence: 74%

“…Notably, all three reports have shown simultaneous deletions of surrounding genes, either upstream or downstream, in the presence of an L1CAM whole gene deletion. While some of the genes involved do not appear to cause additional symptoms, the deletion of the AVPR2 gene results in NDI, which can be life threatening [Knops et al, ; Anesi et al, ]. Therefore, characterization of the breakpoints looking for larger deletions that include AVPR2 for individuals with suspected L1CAM whole gene deletions is recommended.…”

Section: Discussionmentioning

confidence: 99%

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L1CAM whole gene deletion in a child with L1 syndrome

Chidsey

Baldwin

Toydemir

et al. 2014

American J of Med Genetics Pt A

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L1 syndrome is a group of overlapping, X-linked disorders caused by mutations in L1CAM. Clinical phenotypes within L1 syndrome include X-linked hydrocephalus with stenosis of the aqueduct of sylvius (HSAS); mental retardation, adducted thumbs, shuffling gait, and aphasia (MASA) syndrome; spastic paraplegia type 1; and agenesis of the corpus callosum. Over 200 mutations in L1CAM have been reported; however, only a few large gene deletions have been observed. We report on a 4-month-old male with a de novo whole gene deletion of L1CAM presenting with congenital hydrocephalus, aqueductal stenosis, and adducted thumbs. Initial failure of L1CAM gene sequencing suggested the possibility of a whole gene deletion of L1CAM. Further investigation through chromosome microarray analysis showed a 62Kb deletion encompassing the first exon of the PDZD4 gene and the entire L1CAM gene. Investigations into genotype-phenotype correlations have suggested that mutations leading to truncated or absent L1 protein cause more severe forms of L1 syndrome. Based on the presentation of the proband and other reported patients with whole gene deletions, we provide further evidence that L1CAM whole gene deletions result in L1 syndrome with a severe phenotype, deletions of PDZD4 do not cause additional manifestations, and that X-linked nephrogenic diabetes insipidus reported in a subset of patients with large L1CAM deletions results from the loss of AVPR2.

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Section: Discussionsupporting

confidence: 86%

Section: Introductionmentioning

confidence: 74%

Section: Discussionmentioning

confidence: 99%

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L1CAM whole gene deletion in a child with L1 syndrome

Chidsey

Baldwin

Toydemir

et al. 2014

American J of Med Genetics Pt A

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“…It is particularly noteworthy that X-ray bone age was smaller than the actual age of the proband. To our knowledge, short stature is one common feature in some severe NDI cases, compared with twelve other NDI cases previously reported [ 3 , 5 – 11 , 15 ]. It is consistent with the hypothesis that AVPR2 is expressed in osteoblasts and osteoclasts and loss of AVPR2 function would affect bone remodeling [ 16 ].…”

Section: Discussionmentioning

confidence: 59%

Contiguous 22.1-kb deletion embracing AVPR2 and ARHGAP4 genes at novel breakpoints leads to nephrogenic diabetes insipidus in a Chinese pedigree

2018

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BackgroundIt has been reported that mutations in arginine vasopressin type 2 receptor (AVPR2) cause congenital X-linked nephrogenic diabetes insipidus (NDI). However, only a few cases of AVPR2 deletion have been documented in China.MethodsAn NDI pedigree was included in this study, including the proband and his mother. All NDI patients had polyuria, polydipsia, and growth retardation. PCR mapping, long range PCR and sanger sequencing were used to identify genetic causes of NDI.ResultsA novel 22,110 bp deletion comprising AVPR2 and ARH4GAP4 genes was identified by PCR mapping, long range PCR and sanger sequencing. The deletion happened perhaps due to the 4-bp homologous sequence (TTTT) at the junctions of both 5′ and 3′ breakpoints. The gross deletion co-segregates with NDI. After analyzing available data of putative clinical signs of AVPR2 and ARH4GAP4 deletion, we reconsider the potential role of AVPR2 deletion in short stature.ConclusionsWe identified a novel 22.1-kb deletion leading to X-linked NDI in a Chinese pedigree, which would increase the current knowledge in AVPR2 mutation.

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“…Our patient was diagnosed with NDI on the basis of typical neonatal manifestations. Therapeutically, she received treatment with hydrochlorothiazide, amiloride, and indomethacin (Anesi, Gemmis, Galla, & Hladnik, ; Bichet et al, ; Olesen, Rutzler, Moeller, Praetorius, & Fenton, ; Wesche et al, ). Moreover, she received potassium, magnesium, and ranitidine.…”

Section: Discussionmentioning

confidence: 99%

Severe congenital nephrogenic diabetes insipidus in a compound heterozygote with a new large deletion of the AQP2 gene. A case report

Peces

Mena

Peces

et al. 2019

Molec Gen & Gen Med

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Background Congenital nephrogenic diabetes insipidus (NDI) is a rare condition characterized by severe polyuria, due to the inability of the kidneys to concentrate urine in response to arginine vasopressin (AVP). In the majority of the cases, the disease shows an X‐linked inherited pattern, although an autosomal recessive inheritance was also observed. Methods We report a patient with a severe NDI diagnosed during the neonatal period. Because the patient was female without a family history of congenital NDI, her disease was thought to exhibit an autosomal recessive form. Results A full mutation analysis of AVP receptor 2 (AVPR2; MIM#300538) gene showed no mutations. However, direct Sanger sequencing of the aquaporin 2 (AQP2) revealed an apparently homozygous mutation at nucleotide position NM_000486.5:c.374C>T (p.Thr125Met) in exon 2. Further customized multiplex ligation‐dependent probe amplification (MLPA), single‐nucleotide polymorphism (SNP) array analysis, and long‐range polymerase chain reaction (PCR) followed by Sanger sequencing showed a heterozygous exonic deletion comprising exons 2, 3, and partially 4 of AQP2. Conclusion This is the first case of a compound heterozygote patient with a missense mutation involving NM_000486.5:exon2:c.374C>T (p.Thr125Met) and a gross deletion of at least exons 2, 3, and partially 4 on the AQP2 to present with a severe NDI phenotype.

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Two new large deletions of the AVPR2 gene causing nephrogenic diabetes insipidus and a review of previously published deletions

Cited by 15 publications

References 30 publications

L1CAM whole gene deletion in a child with L1 syndrome

L1CAM whole gene deletion in a child with L1 syndrome

Contiguous 22.1-kb deletion embracing AVPR2 and ARHGAP4 genes at novel breakpoints leads to nephrogenic diabetes insipidus in a Chinese pedigree

Severe congenital nephrogenic diabetes insipidus in a compound heterozygote with a new large deletion of the AQP2 gene. A case report

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