title: Novel mutations involving the INSL3 gene associated with cryptorchidism.
abstract: OBJECTIVE
  Cryptorchidism affects 1% to 9% of full-term male neonates. Hypospadias is the second most frequent congenital anomaly seen in newborn males. These pathological conditions are part of the testicular dysgenesis syndrome. Insulin-like factor 3 and LGR8 (leucine-rich repeat-containing G protein-coupled receptor 8), acting as a hormone and a receptor, respectively, are involved in control of the first phase of testicular descent via gubernacular development.
  
  
  METHODS
  The study group consisted of 184 patients, of whom 52 presented with unilateral cryptorchidism, 37 presented with bilateral cryptorchidism, 19 presented with cryptorchidism and hypospadias, 1 presented with bilateral cryptorchidism and micropenis, and 75 presented with isolated hypospadias. A control panel consisted of 270 controls, including 127 fertile, and 143 fertile noncryptorchid males. Insulin-like factor 3 mutations were analyzed by direct sequencing and restriction enzyme digestion. We analyzed the ability of the mutant insulin-like factor 3 peptides identified in this study to activate LGR8 receptor in an ex vivo assays.
  
  
  RESULTS
  We identified 3 novel insulin-like factor 3 variants, including C-19G, V18M and R105H, in 3 of the 109 patients (2.75%) but in none of the 270 controls. The V18M mutation in the insulin-like factor 3 signal peptide had a significant deleterious effect in activating LGR8 receptor in ex vivo studies (p<0.05). To our knowledge we report the first variant in the promoter region of the insulin-like factor 3 gene in a patient with cryptorchidism in association with micropenis.
  
  
  CONCLUSIONS
  Mutations involving the insulin-like factor 3 gene may contribute to other anomalies of male genital development, such as micropenis.
authors: Human Genetics Department, Institut Pasteur of Morocco, Casablanca, Morocco.
authors: Brahim
authors: B
authors: El Houate
authors: Hassan
authors: H
authors: Rouba
authors: Hicham
authors: H
authors: Sibai
authors: Abdelhamid
authors: A
authors: Barakat
authors: Abdelaziz
authors: A
authors: Chafik
authors: El Bekkay
authors: el B
authors: Chadli
authors: Laila
authors: L
authors: Imken
authors: Natalia V
authors: NV
authors: Bogatcheva
authors: Shu
authors: S
authors: Feng
authors: Alexander I
authors: AI
authors: Agoulnik
authors: Ken
authors: K
authors: McElreavey
mesh_terms: D000015:Abnormalities, Multiple / Q000235:genetics; D002648:Child; D003456:Cryptorchidism / Q000235:genetics* / Q000378:metabolism; D004247:DNA / Q000235:genetics*; D015870:Gene Expression; D020022:Genetic Predisposition to Disease; D006801:Humans; D007021:Hypospadias / Q000235:genetics; D007328:Insulin / Q000235:genetics*; D008297:Male; D009154:Mutation; D016366:Open Reading Frames; D010413:Penis / Q000002:abnormalities; D016133:Polymerase Chain Reaction; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D011506:Proteins / Q000235:genetics*; D043562:Receptors, G-Protein-Coupled / Q000235:genetics
chemical_list: D007328:Insulin; C084797:Leydig insulin-like protein; D011506:Proteins; C472867:RXFP2 protein, human; D043562:Receptors, G-Protein-Coupled; D004247:DNA