Androgen receptor dysfunction as a prevalent manifestation in young male carriers of a FLNA gene mutation

Abstract

Androgenic actions require the proper signal transmission by the androgen receptor (AR), a nuclear transcription factor. This is initially located in the cell cytoplasm and should translocates to the nucleus to interact with DNA. AR functional impairment causes diverse blockage degrees of androgenic steroid action, known as androgen insensitivity syndromes. Filamin A, a protein coded by the FLNA gene, is a co-activator of various cytoplasmic factors, including AR. The mutational inactivation of the FLNA gene induces insufficiency of translocation and activation of AR. Consequently, it causes a developmental disorder of the male gonad and hypogonadism, similar to those observed in partial androgen insensitivity. We report two brothers carrying a loss-of-function mutation of FNLA with gonadal differentiation disorder and hypospadias. Specific staining for AR shows almost an absolute absence of these receptors in the testicular tissue. This association recommends investigating a possible mutational inactivation of the FLNA gene in patients with cryptorchidism and epididymo-testicular dissociation. The study is especially indicated when the family history, more often that of the mother, is suggestive. Likewise, growth and gonadal development of all male patients carrying this genetic trait should be monitored since childhood.

<i>PTPN11</i> and <i>FLNA</i> variants in a boy with ambiguous genitalia, short stature, and non-specific dysmorphic features

“…Although 46,XY DSD is not a common symptom of patients with FLNA mutations, hypospadias and cryptorchidism have been reported in a few cases (7,8,17). Importantly, Carrera-Garcia et al proposed that FLNA is involved in the nuclear translocation and activation of the androgen receptor (17). Hence, the p.Pro480Leu variant in our patient may have caused his 46,XY DSD phenotype by affecting the androgen signaling pathway.…”

“…Loss-of-function variants of FLNA have been causally associated with neurodevelopmental and skeletal disorders (15,16). Although 46,XY DSD is not a common symptom of patients with FLNA mutations, hypospadias and cryptorchidism have been reported in a few cases (7,8,17). Importantly, Carrera-Garcia et al proposed that FLNA is involved in the nuclear translocation and activation of the androgen receptor (17).…”

“…Importantly, Carrera-Garcia et al . proposed that FLNA is involved in the nuclear translocation and activation of the androgen receptor ( 17 ). Hence, the p.Pro480Leu variant in our patient may have caused his 46,XY DSD phenotype by affecting the androgen signaling pathway.…”

Syndromic male subfertility: A network view of genome–phenome associations

“…The cataloged genetic variations were divided into two groups: (1) sequence variations in genes and (2) numerical and structural variations in chromosomes. The catalog (Table 1) contains: (1) the names of 63 syndromes alongside 58 identification numbers from the OMIM database (MIM ID) and two from Orphanet (ORPHAcode), (2) the names of 93 associated genes and 93 corresponding gene identification numbers from the NCBI gene database (Gene ID), and (3) 64 NCBI PubMed identification numbers (PMID) of references 26–89 reporting syndromes with male infertility. Retrieved references described patients diagnosed with the syndrome and confirmed subfertility/infertility.…”

A classification of genes involved in normal and delayed male puberty

“…This nongenomic signaling regulates the propagation and survival of cells. 137 Supplementary Table 8 represents the list of 115 genes that have a role to play in the action of steroid hormones 138 – 140 and mutations in 5 genes have been identified to cause delayed puberty 26 , 66 , 76 , 119 , 141 ( Table 1 ).…”