FSHp Subunit

Only four women and three men with a total of four different inactivating mutations of the FSHfi gene have so far been described in the literature (34-38,51) (Table 1). All four women had similar phenotypes, with slightly variable severity, including sexual infantilism, lack of follicular development, and infertility, which are readily explained by the lack of FSH action on granulosa cell estrogen production and progression of follicular maturation beyond the early stages. The phenotypes of the three men with FSHfi mutation (35,37,38,52), are discussed in the section on FSH-R mutations in more detail because they present a conundrum when compared with all other findings concerning the phenotypic effects of inactivation of FSH action in men and male experimental animals.

Of the reports of the three men with inactivating FSH3 Mutations, the one from Sweden described a 32-yr-old man of Serbian origin who presented with azoospermia, normal puberty and male physical characteristics, and a selective FSH absence (37,52). His serum testosterone level was low normal (11 nmol/L) and LH was slightly elevated (12 IU/L). These findings may result from the small size of his testes (3mL/6mL) and the missing FSH effect on their growth at puberty.

Genetic analysis demonstrated a homozygous T to C mutation, predicting a Cys82Arg substitution in the FSH3 protein. It was postulated that the elimination of a cysteine would impair formation of the proper intramolecular disulphide bond of FSH3. This would result in abnormal tertiary structure during FSH3 synthesis, with extensive intracellular degradation, inability to dimerize with the a-subunit, defective glycosylation, and, finally, inability to form biologically active hormone.

The second male, reported from Israel (35), was an 18-yr-old with slight delay of puberty, small testes, azoospermia, and a plasma FSH concentration below 0.5 IU/L. Total testosterone was low (4.5 nmol/L), and LH was increased (24.5 IU/L), indicating a defect in testosterone biosysthesis. DNA sequencing revealed the same homozygous 2 bp deletion in codon 61 that was found previously in the female patients (34,36,38). The mutation gave rise to a completely altered amino acid sequence between codons 61 and 86 of the FSH3 chain, which was followed by a premature stop codon, and lack of translation of amino acids 87 to 111. Consequently, the translated FSH3 protein was truncated and unable to associate with common ¡-subunit to form bioactive or immunoreactive a/3 dimers.

The third man with inactivating FSH3 mutation, described from Brazil (45), had had normal puberty but presented with infertility resulting from azoospermia. His serum testosterone at the age of 30 yr was normal (26 nmol/L), FSH was low, and LH was elevated. His testes were small (12 mL), and testicular biopsy revealed Leydig cell hyper-plasia (LCH) and sparse, small seminiferous tubules with germinal cell aplasia, peritubular fibrosis, and few Sertoli cells. The C to A mutation in codon 76 of his FSH3 gene brought about a premature stop codon (TAA). Because the phenotype of the female patient reported with this mutation was less severe than those of women with the other FSH3 mutations (41,43), it was hypothesized that the missing amino acids 76-110 of FSH3 may not bring about complete inactivation of FSH action (45).

Table 1

List of Currently Known Mutations and Polymorphisms in Human Glycoprotein Hormone Subunit Genes

Table 1

List of Currently Known Mutations and Polymorphisms in Human Glycoprotein Hormone Subunit Genes

Gene

Location

Type

Nucleotide change

Amino acid change

Symptoms inpatient(s)*

Functional effect

Reference

Common a

Exon 3

Missense

CA239G^CCG

Glu56^Ala

Carcinoma

No association with ß-subunit

26

LHß

Exon 3

Missense

CA221G ^CGG

Gln54^ Arg

Infertility, delayed puberty

No binding to receptor

27

LHß

Exon 2

2 missense}

T82GG ^ CGG

Trp8^ Arg

Slighty supressed fertility

Increased in vitro bioactivity

28-30

mutations }

AT104C^ ACC

Ile15^ Th

Association with PCOS?

Short half

Delayed tempo of puberty

LHß

Exon 3

Missense

A1502GT^GGT

Ser102^Gly

Infertility

Not detected

31

LHß

Exon 3

Missense

G52CA^ACA

Ala-3^Thr

Not studied

Slight decrease in signal

32

transduction activity

hCGß

Exon 3

Missense

G295TG^ATG

Val79Met

Not studied

Insufficient assembly

33

with a-subunit

FSHß

Exon 3

2-bp

GTG^GX236,237

Val61 ^STOP87

Prim. amenorrhea, infertility

Truncated protein

34, 35

deletion

Azoospermia

FSHß

Exon 3

Missense

T206GT^GGT

Cys51^Gly

Prim, amenorrhea, infertility

Faulty tertiary

36

structure of protein

FSHß

Exon 3

Missense

T298GT^CGT

Cys82^Arg

Azoospermia

Faulty tertiary

37

structure of protein

FSHß

Exon 3

Nonsense

TAC282^TAA

Tyr76^STOP87

Prim. amenorrhea, infertility

Loss of bioactivity

38

Azoospermia

FSHß

Exon 3

Silent

TAT228^TAC

No change (Tyr)

High FSH, association

Not detected

The nucleotide number was counted according to the translation start site (40), the intronic sequences are excluded. *Findings on male subjects in italic.

with PCOS?

The nucleotide number was counted according to the translation start site (40), the intronic sequences are excluded. *Findings on male subjects in italic.

Conspicuously, all three men with the FSHfi mutation were azoospermia As elaborated in the section on FSH-R mutations, this is not the case with the five men reported to carry homozygous inactivating mutations in the FSH-R gene (53). They each displayed variable suppression of spermatogenesis but were not azoospermic. Neither were the KO mice for FSHfi (54) or FSH-R (55,56) azoospermic, and, moreover, the pheno-types of women with inactivating FSHfi and FSH-R mutation were practically identical (34,36,38,57). The more severe phenotype of the ligand mutation in men is curious also for the reason that animal data show the opposite (58), most likely because of the slight constitutive activity of FSHR in the absence of ligand. Why then are the three men with FSHfi mutation azoospermic? This is discussed next in more detail in connection with FSH-R mutations.

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