Novel mutations involving the INSL3 gene associated with cryptorchidism.
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.
El Houate
Brahim
B
Human Genetics Department, Institut Pasteur of Morocco, Casablanca, Morocco.
Rouba
Hassan
H
Sibai
Hicham
H
Barakat
Abdelhamid
A
Chafik
Abdelaziz
A
Chadli
El Bekkay
el B
Imken
Laila
L
Bogatcheva
Natalia V
NV
Feng
Shu
S
Agoulnik
Alexander I
AI
McElreavey
Ken
K
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
D007328:Insulin; C084797:Leydig insulin-like protein; D011506:Proteins; C472867:RXFP2 protein, human; D043562:Receptors, G-Protein-Coupled; D004247:DNA