Unusual Phenotypic Features in a Patient with a Novel Splice Mutation in the GHRHR Gene

Hilal, Latifa; Hajaji, Yassir; Vié-Luton, Marie-Pierre; Ajaltouni, Zeina; Benazzouz, Bouchra; Chana, M.; Chraïbi, A.; Kadiri, A.; Amselem, Serge; Sobrier, Marie-Laure

doi:10.2119/2007-00128.hilal

Cited by 31 publications

(15 citation statements)

References 40 publications

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“…These 105 IGHD individuals through seven generations from the rural county of Itabaianinha have a homozygous mutation in the consensus GT of the 5 splice site of intron 1, required for correct splicing of intron 1 from RNA transcripts (c.57 + 1G>A). This mutation likely leads to retention of intron 1 and insertion of a premature stop codon 213 bases from the exon-intron junction, similarly to what was later described for a different mutation in the same splice site [10]. A founder effect has been hypothesized in this population, in which the high incidence of consanguineous unions seems to be the principal cause for mutation spread [6].…”

Section: Ghrh Gene Mutationssupporting

confidence: 66%

Molecular and Clinical Aspects of GHRH Receptor Mutations

Corazzini

Salvatori²

2013

Hormone Resistance and Hypersensitivity

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The growth hormone (GH)-releasing hormone (GHRH) receptor (GHRHR) belongs to the G protein-coupled receptor family. It binds GHRH resulting in somatotroph cell proliferation and stimulation of GH secretion. Mutations in the gene encoding for GHRHR (GHRHR, OMIM No. 139191) are being reported with increasing frequency in familial isolated GH deficiency. To date, the reported GHRHR mutations include eight missense, seven splice, three microdeletions, and two non-sense mutations. One promoter mutation has also been reported. Most of these mutations show a recessive mode of inheritance. The phenotype includes reduced but not absent serum GH, with abnormal response to a variety of stimuli, and low serum insulin-like growth factor-1 levels, resulting in proportionate growth failure which becomes evident in the first year of life. These patients respond well to GH replacement therapy. Phenotypical observations coming from some unusually large kindreds with untreated GH deficiency due to homozygous GHRHR mutations have allowed the study of the consequences of lifetime lack of GH. This chapter reviews the structure and the role of the GHRHR together with the clinical aspects associated with its mutations.

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Section: Ghrh Gene Mutationssupporting

confidence: 66%

Molecular and Clinical Aspects of GHRH Receptor Mutations

Corazzini

Salvatori²

2013

Hormone Resistance and Hypersensitivity

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“…These include twin studies [1], [10], [11], [12], [13], [14], [15], [16], familial clustering [10], [14], [15], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], and co-segregation with known genetic syndromes or conditions commonly found as part of a genetic syndrome, including Ehlers-Danlos syndrome [9], [31], [32], [33], Marfan syndrome [9], [34], [35], [36], Klippel-Feil syndrome [23], [37], [38], [39], [40], [41], [42], [43], [44], [45], [46], [47], [48], growth hormone deficiency [45], [46], [49], [50], [51], [52], [53], [54], [55], craniosynostosis [56], [57], and Neurofibromatosis type I [58], [59]. Furthermore, in a study conducted by Milhorat and colleagues, it was reported that out of a cohort of 364 symptomatic patients, 43 (12%) had at least one close relative with CMI with or without syringomyelia or idi...…”

Section: Introductionmentioning

confidence: 99%

Stratified Whole Genome Linkage Analysis of Chiari Type I Malformation Implicates Known Klippel-Feil Syndrome Genes as Putative Disease Candidates

et al. 2013

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Chiari Type I Malformation (CMI) is characterized by displacement of the cerebellar tonsils below the base of the skull, resulting in significant neurologic morbidity. Although multiple lines of evidence support a genetic contribution to disease, no genes have been identified. We therefore conducted the largest whole genome linkage screen to date using 367 individuals from 66 families with at least two individuals presenting with nonsyndromic CMI with or without syringomyelia. Initial findings across all 66 families showed minimal evidence for linkage due to suspected genetic heterogeneity. In order to improve power to localize susceptibility genes, stratified linkage analyses were performed using clinical criteria to differentiate families based on etiologic factors. Families were stratified on the presence or absence of clinical features associated with connective tissue disorders (CTDs) since CMI and CTDs frequently co-occur and it has been proposed that CMI patients with CTDs represent a distinct class of patients with a different underlying disease mechanism. Stratified linkage analyses resulted in a marked increase in evidence of linkage to multiple genomic regions consistent with reduced genetic heterogeneity. Of particular interest were two regions (Chr8, Max LOD = 3.04; Chr12, Max LOD = 2.09) identified within the subset of “CTD-negative” families, both of which harbor growth differentiation factors (GDF6, GDF3) implicated in the development of Klippel-Feil syndrome (KFS). Interestingly, roughly 3–5% of CMI patients are diagnosed with KFS. In order to investigate the possibility that CMI and KFS are allelic, GDF3 and GDF6 were sequenced leading to the identification of a previously known KFS missense mutation and potential regulatory variants in GDF6. This study has demonstrated the value of reducing genetic heterogeneity by clinical stratification implicating several convincing biological candidates and further supporting the hypothesis that multiple, distinct mechanisms are responsible for CMI.

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“…To date, approximately 20 different GHRHR mutations have been described in patients with this condition. [6][7][8][9][10][11][12][13][14][15][16][17][18][19][20] Previous studies have demonstrated diverse molecular mechanisms by which homozygous and compound heterozygous mutations lead to a loss of GHRHR function. Nonsense and splicing mutations are expected to produce a truncated receptor or to cause mRNA instability.…”

Section: Introductionmentioning

confidence: 99%